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Patient and physician attitudes regarding clinical trials in neurofibromatosis 1.

Abstract: Neurofibromatosis 1 (NF1) is a multisystem genetic disorder that primarily affects the skin (freckling and cafe-au-lait macules), nervous system (neurofibromas, optic gliomas, and learning disabilities), and skeletal system (pseudoarthroses). The interest in pharmacological intervention for patients with NF1 has grown in recent years. However, little is known about the attitudes and priorities of patients, families, and physicians regarding participation in clinical trials. We surveyed 74 adult patients or parents of patients with NF1 and 69 care providers participating in a neurofibromatosis clinic to assess their willingness to participate in clinical trials and their opinions about which conditions they thought were most important to treat. Both patients and care providers are willing to participate in clinical trials for NF1 and both groups rate malignant peripheral nerve sheath tumors as the most urgent for new treatments. There are concordant views among patients and physicians concerning clinical trials for NF1, and patients do not dismiss participation in placebo-controlled trials. Neuroscience nurses are poised to facilitate the research process from conception through implementation as they take the viewpoints of our study populations into consideration.

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Neurofibromatosis 1 (NF1) is one of the most common dominantly inherited genetic disorders, affecting approximately 1 in 3,000 people (Lammert, Friedman, Kluwe, & Mautner, 2005; Rasmussen & Friedman, 2000). NF1 is a multisystem disorder that primarily affects the skin (freckling and cafe-au-lait macules), nervous system (benign and malignant nerve sheath tumors, optic gliomas, and learning disabilities), and skeletal system (pseudoarthroses; DeBella, Szudek, & Friedman, 2000; Huson, Harper, & Compston, 1988; King, Debaun, Riccardi, & Gutmann, 2000). Attitudes toward clinical trials have been examined in the general public and in specialties such as oncology (Comis, Miller, Aldige, Krebs, & Stoval, 2003; Eggly et al., 2008; Melisko et al., 2005; Meropol et al., 2007; Ohmann & Deimling, 2004), but little is known about the attitudes and priorities of patients, families, and physicians regarding participation in clinical trials for neurogenetic conditions. With limited resources for clinical trials, researchers must prioritize which manifestations of NF1 to target. Because physician recommendation is vital to patient enrollment (Eggly et al.), clinical trials must be designed so specialists who care for these patients will encourage study participation and refer subjects to research sites. Consequently, we assessed patient and physician attitudes regarding clinical trials in NF1 under a Massachusetts General Hospital (MGH) institutional review board-approved protocol.

Methods

An anonymous patient survey (Fig 1) featuring questions designed to assess demographics and subjective disease severity (four questions), attitudes toward treatment of specific manifestations of NF1 (one question), and attitudes toward clinical trial participation (four questions) was mailed to 150 unrelated NF1 patients or the parents of minor patients seen at the MGH Neurofibromatosis Clinic. A coded survey (Fig 2) was mailed to 104 physicians who identified themselves as referral physicians for neurofibromatosis (NF) on a national patient support group Web site (Children's Tumor Foundation, www.ctf.org). This survey featured questions designed to assess demographic practice information (four questions), attitudes toward treatment of specific manifestations of NF1 (one question), willingness to participate in various clinical trial scenarios (three questions), and perceived barriers to clinical trials in NF1 (one question). Descriptive statistics were used to summarize participant responses. Responses to patient and physician surveys additionally were analyzed in two complementary ways. The percentage of respondents that ranked each manifestation as most important was compared to identify the collective top priority, and the average rank order was calculated to discriminate between manifestations not identified as top priority. Multivariate logistic regression was used to test for association between respondents' willingness to participate in clinical trials (Question 6 on the patient survey and Question 7 on the physician survey) and demographic characteristics such as age, gender, and disease severity for patients, and specialty years in practice for physicians.
Fig 1. Patient Survey

1. What is your age (or the age of the child for whom you are
filling out this survey) in years as of January 1, 2005?

2. Please indicate your gender (Circle one): Male Female

3. How many members of your immediate family (for example, parents,
brothers or sisters, children) have been diagnosed with NF1?--

4. Please rate the severity of your/your child's symptoms related
to NF1 (Circle one.)

1 2 3 4 5
(No symptoms) (Severe symptoms)

5. In your opinion, how important are clinical trials (drug
studies) to the field of neurofibromatosis? (Circle one.)

1 2 3 4 5
(Not important) (Extremely important)

6. Would you be willing to participate in a clinical trial? If you
are answering for your child, would you be willing to allow your
child to participate? (Check one): --Yes --No

If you answered "yes" to question 6 above, please answer questions
7-9. If you answered "no" to question 6, you have finished the
questionnaire.

7. Please rank the problems associated with NF1 listed below in
order of what you feel is most important to treat (1 is the most
important, 6 is the least important). Skin tumors

--Plexiform neurofibromas (deep nerve tumors)

--Malignant peripheral nerve sheath tumors (cancer from a nerve
tumor)

--Optic gliomas (tumors behind the eye)

--Cafe-au-lait macules (birth marks associated with NF1)

--Learning disability (learning problems)

8. Please indicate the maximum amount of time you or your child
would be willing to dedicate to a clinical trial. (Check one.)

--1 visit per week

--1 visit every 2 weeks

--1 visit per month

--1 visit every 2 months

--1 visit every 3 months

9. Would you be willing to participate in a drug study in which
half of the subjects received a study drug and half received a
sugar pill (placebo)? (Check one.)

--Yes

--No

--Not sure

Note. NF1 = neurofibromatosis 1.


Results

Seventy-four patient or parent responses (49% response rate) and 69 provider responses (66% response rate) were received. Guardians of children under 18 years of age represented 20% of patient respondents (n = 15).
--Fig 2. Physician Survey

1. Please indicate your gender. (Check one.)

2. What is your medical specialty? (Check one.)--Male --Female

--Adult neurology --Pediatric neurology
--Internal medicine --Pediatrics
--Adult oncology --Pediatric oncology
--Neurosurgery --Genetics
--Other (please list)--

3. Please indicate the average volume of patients with NF1 that
you see in clinic. (Check one.)

--<1/month --1-5/month --6-10/month --11-15/month -- >15/month

4. Please indicate how long you have been a specialist for patients
with NF1. (Check one.)

--Not a specialist

--1-5 years

--6-10 years

--11-15 years

-->15 years

5. Please rank the following manifestations of NF1 in order of
importance to treat if a clinical trial were to open (1 is most
important and 6 is least important):

--Skin tumors

--Plexiform neurofibromas

--Malignant peripheral nerve sheath tumors

--Optic gliomas

--Cafe-au-lait macules

--Learning disability

6. Would you be willing to enroll patients in a placebo-controlled
clinical trial?

--Yes

--No

7. Would you enroll patients in a clinical trial that involved
an over-the-counter drug (as opposed to prescribing it off-study)?

--Yes

--No

8. In your opinion, how significant are the following barriers to
implementing clinical trials for NF1?

 (Not (Very
 significant) significant)

Lack of patient interest 1 2 3 4 5
Lack of adequate patient numbers 1 2 3 4 5
Lack of resources at your
 institution 1 2 3 4 5
Lack of interesting drugs to study 1 2 3 4 5
Other (please list)-- 1 2 3 4 5

9 If a clinical trial for patients with NF1 were not open at your
center, would you refer a potentially eligible patient to
another center sponsoring the trial?

--Yes --No

Note. NF1 = neurofibromatosis 1.


Patients with NF1 Are Willing to Participate in Placebo-Controlled Clinical Trials

The majority of patient respondents (57%) were women (median age 34.5 years), and 41% noted a family history of NF1. The median subjective disease severity was 3.0 (moderate symptoms), indicating that respondents were not limited to mildly or severely affected subpopulations. A majority (89%) classified clinical trials as very important or extremely important, and 67% would enroll themselves or their child. Only 20% would not enroll in a trial. Of those willing to participate (n = 58), 62% and 100%, respectively, would attend a study visit every month or every 3 months. Among those willing to participate in clinical trials, 48% would do so in a placebo-controlled trial, while 44% were unsure and fewer than 5% were unwilling to participate in a placebo-controlled trial. Demographics and disease severity did not reveal any factors associated with willingness to participate by multivariate logistic regression (SAS Statistical Program, SAS Institute, Cary, NC). Malignant peripheral nerve sheath tumor (MPNST) was ranked as the most important manifestation to treat by the highest percentage of patients (39%) and achieved the highest average rank (2.41). MPNST was followed in order by plexiform neurofibroma, optic glioma, skin tumors, learning disabilities, and cafe-au-lait macules (Table 1).

Physicians Support Placebo-Controlled Trials for NF1

The majority of physician respondents were men (58%). Genetics was their most common specialty (64%), followed by pediatric neurology (12%) and adult neurology (7%). More than half (54%) of respondents delivered specialized NF care for 15 or more years, and 28% had been doing so for 6-15 years. Ninety-four percent of physicians (n = 64) were willing to enroll their patients in placebo-controlled clinical trials, while 4% (n = 3) were not. MPNST again was overwhelmingly ranked as the most important condition to treat (49%) with an average rank of 1.95, followed in order by plexiform neurofibroma, optic glioma, and learning disabilities. No physicians ranked skin tumors or cafe-au-lait macules as most important to treat (Table 1). Physicians perceived the lack of scientifically interesting study drugs (67%) and a lack of institutional resources (41%) as significant barriers to clinical trials, though a minority cited a lack of patient numbers (22%) or patient interest (14%) as barriers. Almost all physicians (90%) said they would refer a potentially eligible patient to another center if a trial were not open at their center.

Discussion

Though the study sample was modest in size and patients drawn from one tertiary referral center may not represent all patients with NF1, our findings highlight the importance of surveying patients and care providers during the clinical trial design process. Patients and care providers alike are willing to participate in clinical trials for NF1 even though the disorder is primarily characterized by benign tumors. Moreover, patients and physicians fundamentally agree on which manifestations of NF1 are most important to treat, with MPNST, plexiform neurofibromas, and optic gliomas rated as top priorities for both groups. Patients are more likely than physicians (31% versus 3%) to rank manifestations that cause morbidity (skin tumors, learning disabilities, and cafe-au-lait macules) as most important. At the present time, physicians perceive a lack of promising study drugs as the major barrier to clinical trials in NF1. This situation is changing rapidly given the introduction of targeted drugs for cancer treatment during the past decade.

While fewer patients indicated willingness to participate in placebo-controlled clinical trials (rather than nonplacebo-controlled trials), few patients stated unwillingness. This indicates that a large group of NF1 patients would consider participating in placebo-controlled trials based on the details of individual trials.

Neuroscience nurses work with patients with NF1 on many levels. As trusted healthcare professionals, nurses are in a crucial position to support clinical trials through study design, implementation with research colleagues, and patient participation. Neuroscience nurses need to know that patients with NF1 have demonstrated willingness to participate in clinical trials, and they believe such studies are important. Further, these patients place more emphasis on the elements of their condition that cause morbidity than do their physicians. Neuroscience nurses are poised to direct the research process from conception through implementation, taking the viewpoints of our study populations into consideration.

Conclusions

Patients and care providers are willing to participate in clinical trials for NF1 and they agree on which manifestations are most important to treat. Patients and physicians also are willing to participate in placebo-controlled trials. Neuroscience nurses are vital to the clinical research performed that can improve the symptoms that cause extensive morbidity and mortality for this vulnerable population. Further studies are needed to determine patient and care provider attitudes toward clinical trials for other neurogenetic conditions.

Acknowledgments

This work was supported by grants to James Gusella, PhD, from Neurofibromatosis Inc., New England, and from the Alsam Foundation.

References

Comis, R. L., Miller, J. D., Aldige, C. R., Krebs, L., & Stoval, E. (2003). Public attitudes toward participation in cancer clinical trials. Journal of Clinical Oncology, 21(5), 830-835.

DeBella, K, Szudek, J., & Friedman, J. M. (2000). Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics, 105(3 Pt. 1), 608-614.

Eggly, S., Albrecht, T. L., Harper, F. W., Foster, T., Franks, M. M., & Ruckdeschel, J. C. (2008). Oncologists' recommendations of clinical trial participation to patients. Patient Education and Counseling, 70(1), 143-148.

Huson, S. M., Harper, P. S., & Compston, D. A. (1988). Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain, 111 (Pt. 6), 1355-1381.

King, A. A., Debaun, M. R., Riccardi, V. M., & Gutmann, D. H. (2000). Malignant peripheral nerve sheath tumors in neurofibromatosis 1. American Journal of Medical Genetics, 93(5), 388-392.

Lammert, M., Friedman, J. M., Kluwe, L., & Mautner, V. F. (2005). Prevalence of neurofibromatosis I in German children at elementary school enrollment. Archives of Dermatology, 141, 71-74.

Melisko, M. E., Hassin, F., Metzroth, L., Moore, D. H., Brown, B., Patel, K., et al. (2005). Patient and physician attitudes toward breast cancer clinical trials: Developing interventions based on understanding barriers. Clinical Breast Cancer, 6(1), 45-54.

Meropol, N. J., Buzaglo, J. S., Millard, J., Damjanov, N., Miller, S. M., Ridgway, C., et al. (2007). Barriers to clinical trial participation as perceived by oncologists and patients. Journal of the National Comprehensive Cancer Network, 5(8), 655-664.

Ohmann, C., & Deimling, A. (2004). Attitude towards clinical trials: Results of a survey of persons interested in research. Inflammation Research, 53(Suppl. 2), S142-S147.

Rasmussen, S. A., & Friedman, J. M. (2000). NF1 gene and neurofibromatosis 1. American Journal of Epidemiology, 151, 33-40.

Questions or comments about this article may be directed to Scott R. Plotkin, MID PhD, at splotkin@partners.org. He is an assistant professor of neurology at Massachusetts General Hospital Department of Neurology, Boston, MA, and associate member at the Center for Neurofibromatosis and Allied Disorders at Harvard Medical School, Boston, MA.

Mary McQueen, APRN-BC, is a nurse practitioner at the Wardenburg Health Center at University of Colorado at Boulder.

Mia MacCollin, MD, is retired from her position as associate professor at Massachusetts General Hospital Department of Neurology, Boston, MA, and associate member at the Center for Neurofibromatosis and Allied Disorders at Harvard/Medical School, Boston, MA.

James Gusella, PhD, is director of the Center for Neurofibromatosis and Allied Disorders at Harvard Medical School, Boston, MA, and director of the Massachusetts General Hospital Center for Human Genetic Research, Boston, MA.
Table 1. Patient and Physician Ranking of Importance to Treat Various
Manifestations of Neurofibromatosis 1

 Patient Ranking (n = 74)

 Most Important
Manifestation (95% CI) Average Rank

MPNST 39% (28%-51%) 2.41
Plexiform neurofibroma 17% (10%-28%) 2.74
Optic glioma 8% (3%-17%) 3.19
Skin tumors 10% (5%-20%) 3.47
Learning disabilities 16% (9%-27%) 3.63
Cafe-au-lait macules 10% (5%-20%) 4.85

 Physician Ranking (n = 69)

 Most Important
Manifestation (95% CI) Average Rank

MPNST 49% (37%-62%) 1.95
Plexiform neurofibroma 36% (25%-49%) 2.01
Optic glioma 9% (3%-18%) 2.90
Skin tumors 0% (0%-5%) 4.11
Learning disabilities 2% (0%-8%) 3.90
Cafe-au-lait macules 0% (0%-5%) 5.76

Note. 1 = most important; 6 = least important. 95% binomial
confidence intervals were calculated for each manifestation against
the other five manifestations. CI = confidence interval;
MPNST = malignant peripheral nerve sheath tumor.
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No portion of this article can be reproduced without the express written permission from the copyright holder.
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Article Details
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Author:McQueen, Mary; MacCollin, Mia; Gusella, James; Plotkin, Scott R.
Publication:Journal of Neuroscience Nursing
Geographic Code:1USA
Date:Dec 1, 2008
Words:2617
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