NATIONAL INSTITUTES OF HEALTH (NIH)

Sham Neurosurgical Procedures in Clinical Trials for Neurodegenerative Diseases: Scientific and Ethical Considerations

http://oba.od.nih.gov/rdna_rac/rac_sham_con.html

Open to the public - if i weren't going to have out of town company - I'd be there.

This meeting is very important. Usually these meetings have a few pd advocates from orgs, may a pwp, or FDA patient reps. Improvement is slow; the general pd community rarely hears about the outcomes. Statements about how troubling sham surgery is are basically ignored.

Our scientists insist it is essential; Europe regards it as barbaric.

This time there is better pwp representation from clinical trial participants. But there is never any support. It's asking a lot of a pwp.

If you are at all inclined to get your feet wet in these issues, and if it is at all possible, please try to attend this meeting, even if you don't get in. This issue is worth carrying a sign for.

I'm not saying that you should spend your last dollar to get to DC. But there may be carpooling opportunities or group travel for those who live close enough.

The people involved in this event seem to sincerely want to listen, but as you read the agenda below, you'll see how powerful this panel is - our pwp reps are up against the establishment.

We need numbers or this issue is going nowhere.

Otherwise the status quo will occur. Patients speak, establishment disagrees and ignores.

The Agenda







The randomized, placebo-controlled clinical trial is generally viewed as the gold-standard in clinical investigation. However, when a trial involves a sham surgical procedure, unique scientific and ethical issues emerge. There are several examples of positive findings in open label studies of cell or gene therapies in Parkinson’s disease where subsequent trials which included a sham neurosurgical arm failed to show a difference between treatment arms. While sham neurosurgical arms have often been included in recent gene therapy trials for Parkinson’s disease (four of six that have been initiated since 2003) and Alzheimer’s disease (one trial started enrolling in November of 2008), their use is not without controversy.

As novel therapies are developed for neurodegenerative diseases, questions will arise about whether to include a sham arm and if so, at what stage in development. Institutional Review Boards will continue to face challenges in ethical reviews of such projects, and patients will face complex decisions regarding the risk-benefit ratio.

The Office of Biotechnology Activities, Office of the Director and the National Institute of Neurological Disorders and Stroke have developed this conference to explore the scientific and ethical issues regarding sham neurosurgical arms and to provide a foundation for development of points to consider when designing clinical trials. The specific goals are to:

· Increase our understanding of the utility and limitations of sham neurosurgical procedures through a review of the prior clinical trial experience in Parkinson’s disease.
· Address how experiences from trials in Parkinson’s disease may inform clinical trial design for other neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and Huntington’s disease.

· Discuss the scientific and ethical issues raised by the use of sham neurosurgical procedures, including trial design, subject recruitment, risk assessment, and informed consent.

· Explore the perspective of patients regarding the design of trials that may involve sham neurosurgical procedures.



Wednesday, June 30, 2010

8:00 AM Welcome and Opening Remarks

Howard J. Federoff, M.D., Ph.D., Conference Co-Chair
Anthony Lang, M.D., FRCPC, Conference Co-Chair
Jacqueline Corrigan-Curay, M.D., J.D., Office of Biotechnology Activities, National Institutes of Health
Story Landis, Ph.D., National Institute of Neurological Disorders and Stroke, National Institutes of Health

8:15 AM Clinical Trial Design: Randomization, Controls and Minimizing Bias

Presenter: Karl Kieburtz, M.D., M.P.H.

8:30 AM Clinical Trial Design: Statistical Challenges in Designing Surgical Trials for Neurodegenerative Diseases

Presenter: Steven Piantadosi, M.D., Ph.D.

8:45 AM Insights into Understanding the Placebo Response

Presenter: A. Jon Stoessl, M.D.

9:05 AM Review of Parkinson’s Disease Trials that Did Not Include a Sham Neurosurgical Arm

Fetal Cell Transplantation Trials for Parkinson’s Disease

Presenter: Patrik Brundin, M.D., Ph.D. (by teleconference)

Neurotrophic Factor Trials for Parkinson’s Disease

Presenter: John T. Slevin, M.D.

· What factors were considered in deciding not to include a sham neurosurgical arm?
· What were the ethical considerations, and how did these impact the study design?
· What questions can be answered in the absence of a sham arm? Are there questions that can be answered only with the inclusion of a sham neurosurgical arm?
· Given the results of the subsequent trials, would you design the study differently to answer your original study questions?

· include a “best medical management” arm as well as a sham neurosurgical arm?

Thursday, July 1, 2010

8:00 AM Opening Remarks

Howard J. Federoff, M.D., Ph.D., Co-Chair
Anthony Lang, M.D., FRCPC, Co-Chair

8:20 AM A Patient’s Perspective on the use of Sham Neurosurgical Procedures

Moderator: Howard Federoff, M.D., Ph.D.

Perry Cohen, Ph.D.
· Do you see a role for sham neurosurgical arms in clinical trials? Why or why not?

8:35 AM An Ethical Framework for Evaluating the Use of Sham Neurosurgical Procedures

Presenter: Edmund Pellegrino, M.D.

8:55 AM Ethical Considerations in the Use of Sham Neurosurgical Procedures

Moderator: Anna Mastroianni, J.D., M.P.H.
Panelists: Herbert Gottweis, Ph.D., Jeffrey P. Kahn, Ph.D., M.P.H., Jason H. Karlawish, M.D., Scott Kim, M.D., Ph.D., Jonathan Kimmelman, Ph.D., Edmund Pellegrino, M.D., Dorothy E. Vawter, Ph.D.

Balancing Science and Ethics
· Is the scientific evidence supporting the use of a sham neurosurgical arm to answer the study questions sufficiently robust to justify the risks from an ethical perspective?
Discussion of Risk
· Given the previous discussion of the risks of partial burr holes and stereotactic frames, conscious sedation versus general anesthesia, and additional procedures, e.g. imaging,, is the stage of the research (e.g. Phase I vs Phase II) determinative in deciding whether it is ethically appropriate to include a sham neurosurgical arm?

· Does the ethical analysis regarding subject selection for a trial that uses a sham neurosurgical arm change depending upon the stage or severity of the subject’s disease?
· If previous trials have established that a placebo response to the sham neurosurgical procedure is likely and often sustained for a period of time, does this potential for a benefit from the sham neurosurgery justify an increased level of risk?

· How do cross-over designs influence the ethical analysis?

· In cases without cross-over, when, if ever, do researchers have an obligation to offer access to the active agent to those in the sham arm?

10:10 AM BREAK

10:20 AM Discussion of Informed Consent
· What strategies may be used to minimize therapeutic misconception?
§ How can discussions of risks and benefits be conducted in order to support realistic expectations of potential harms and side effects?
· How important is the potential for investigator bias in influencing therapeutic misconception, and how can such bias and its effects be minimized?

· What special considerations should the informed consent (IC) process address in patients with neurodegenerative diseases where there may be cognitive impairment and/or impaired decision-making capacity?
· If a subject’s capacity to give informed consent is impaired, under what circumstances should they still have access to trials involving the use of sham neurosurgical procedures? What is the role of caregivers in this setting?
11:35 AM Pediatric Trials and Sham Neurosurgical Procedures: Unique Ethical Considerations
Presenter: David Wendler, Ph.D.

Discussants: Ronald G. Crystal, M.D., Eric Kodish, M.D.

12:45 PM LUNCH

1:20 PM Public Comment

1:40 PMTherapeutic Development, Sham Surgery Controls, and Evidence of Effectiveness

Presenter: Wilson W. Bryan, M.D.

2:00 PM Summary Discussion of the Science and Ethics of the Use of Sham Neurosurgical Procedures in Neurodegenerative Diseases

Moderators: Howard J. Federoff, M.D., Ph.D.
Anthony Lang, M.D., FRCPC

· How does the clinical outcome measure affect the need for a sham procedure?

· Are there questions that can only be answered by including sham neurosurgical procedures?

· What is the role of a “standard of care” arm and what factors should be considered in using “standard of care” as a control arm rather than a sham neurosurgical arm?

· Is there a role for both a standard of care and a sham neurosurgical arm?

· How does the evaluation of risk of the sham neurosurgical procedure differ in the context of different neurologic diseases?

· If a sham neurosurgical arm is to be used, what is the optimal study design given the anticipated placebo effect?
§ Degree of invasiveness
§ Anesthesia: conscious sedation vs. general
§ Should additional medications or procedures have a placebo equivalent, e.g., imaging with associated radiation exposure, immunosuppression

· What measures can be taken to minimize placebo effect?

· For Alzheimer’s disease, ALS, and Huntington’s disease, are there validated outcome measures that can be used to evaluate disease progression without the use of a sham arm?

· What are the key ethical considerations when employing a sham neurosurgical arm versus another type of control?

· What special considerations should the informed consent process address in subjects with impaired capacity?

· How can potential subjects be better educated and engaged regarding the role of sham neurosurgical procedures in neurodegenerative disorders?

5:00 PM Closing Remarks

5:15 PM Adjourn
http://oba.od.nih.gov/rdna_rac/rac_sham_con.html

Thanks Jean and Paula for bringing this important, first-of-its-kind conference to our attention. If you can't get to Washington for the conference, the NIH is also acccepting written statements.
"The public can submit comments in advance of the meeting and these will be
made available for review provided they are received at least a week prior to the meeting. "
E-mail your comments to Office of Biotechnology Activity: oba@od.nih.gov

Also the Parkinson Pipeline Project will be conducting an opinion poll on sham surgery -- an update to a poll we did in 2007 of members of Neurotalk (Braintalk ) and the Parkinsn List. Please be on the lookout for our new poll within the next few days and please send us your response. All of our voices should be heard !
Linda