Summit on Clinical Trials, October 27-29, 1999 
Washington, D.C. ( by invitation only)

This meeting was the third in a series designed to bring together various groups involved in clinical trials-third party payers, oncology cooperative groups, patients and advocates, government officials, pharmaceutical companies and the media.

Currently clinical trials are proposed and conducted by either pharmaceutical companies or NCI or the oncology cooperative groups and conducted by individual doctors, NCI or the groups. Local IRB (Institutional Review Boards) oversee patient care, trial design, informed consent forms etc.

The first series of discussions were general with many of the audience standing to discuss problems with the clinical trial system. Deborah Collyar, President of Patient Advocates in Research (a patient herself) discussed trials. She stated that often the perception of a trial is that it is a "last resort" for the patient. It was also said that the trial system was designed for chemotherapy. Deb also made the important point that chemoprevention is a lousy title that turns people off since it refers back to chemotherapy rather than prevention.

Carolyn Aldige gave the audience an overview of a Harris Interactive Poll that will take place via the Internet. Questions will be asked of patients, consumers and medical personnel on their views of clinical trials.

Anne Thurn, PhD and Nancy Seybold, from NCI spoke about the patient information services available over the Internet. or They discussed the PDQ, a system that lists clinical trials. Only 12% of all listings are from pharmaceutical companies, the rest are NCI sponsored trials. This is not good for patients since it would be best to have a complete listing available. The pharmaceutical industry has commented that they have to protect their proprietary information.

Ann’s NOTE: This does not seem like a reasonable point as the PDQ merely states location, primary investigator and drug name/s. I am convinced that most competitors know what is going on at other firms. In fact I said that to Rick Winningham, President of Bristol-Myers Squibb Oncology/Immunology who was at this meeting.

Michael O’Connell, MD spoke about the system capacity. He told the audience that only 2% of the U.S. adult patient population enrolls in clinical trials. The intent is to raise this to 10% participation. The infrastructure would have to be expanded simultaneously, more patients, more clinical research associates, more nurses, community-based doctors , clinical investigators, more promising treatments, protocols as well as operations offices, statisticians and cancer centers.

A further point was that study protocols needed to be simplified, as did logistics and data. Patient eligibility criteria, in fact all elements need simplification. With the increased use of computer systems and the Internet, this seems feasible.

He also said that investigators had learned more in the last 10-15 years than in all recorded history.

Dr. Mary Todd, Deputy Director of the Cancer Institute of New Jersey discuss the system they are implementing within the state. She said that administrative costs of a trial were covered by the institute; the investigational drug is paid for by the sponsor or pharmaceutical company; routine care is covered by the payer (insurance company) and exceptional costs, patient care is covered by the sponsor.

Jeff Abrams, MD, Senior investigator, NCI told the audience that there are eight adult cooperative groups. The four focused on pediatric patients will be merging into one. There are 1500 institutions, 8000 investigators and about 20,000 patients annually. The possibility of more patients involved could reduce the time to discover useful data and would decrease the time it takes to begin a trial.

Alan Keller, MD, Co-medical Director, US Oncology Inc. spoke about their systems. He said they had 7000 employees of which 750 were doctors. They expected to see 160,000 cancer patients in the year 2000. They utilize a central IRB with database management and drug management centrally. Safety and toxicity reporting is made to one location as well. They manage 300 sites.

Rick Winningham, President of Bristol-Myers Squibb Oncology/Immunology Division stated that his company had 374 pre-clinical drugs in the ‘pipeline’. He stated that something like 90% of (past) drug ideas fail. This may be about to change. He suggested that regulatory areas lag behind common knowledge. More patients would be needed to test all the new drug ideas as soon as can be. That way drug trials could be done simultaneously.

Robert Catalano, MD discussed the nature of informed consent. He said it has to explain the purpose of the study-forseeable risks, potential personal benefit, what alternatives are available, how confidentiality works, if there is compensation given for medical care needed in conjunction with the study, names and numbers of contacts.

There has to be awareness that participation is voluntary and the patient can withdraw at any time without penalty or consequences. Also the patient needs to know under what circumstances they could be terminated from the study without their consent needed. The patient has to receive any ‘significant’ new information that arises during the course of the study. There needs to be some education on relative risks due to any cancer treatment and specifically about the trial.

Ann’s NOTES: I have questioned what forseeable risks entails. Unwanted effects ("side" effects) are often dismissed by saying " they were not unexpected". That may be true, but it in no way diminishes the problems. Additionally I wonder what qualifies as significant new information. The Breast Cancer Prevention Trial 1-the first to use healthy volunteers for cancer prevention therapy was stopped due to new information that arose-but many believe that was forced on the organizers (NSABP-National Surgical Breast and Bowel Project) by activists, especially the Women’s Health Network.

It is also my contention that if patients understood that the risks posed in the Informed Consent sheet are sometimes equivalent to that of the conventional treatment they would get on the comparison arm of the trial or as regularly accepted treatment. That is, chemotherapy is toxic to many parts of the body and there are many ‘forseeable’ "side" effects that are fairly lousy for patients.

Richard Schilsky, MD, Chairman of the Cancer and Leukemia Group B (and a member of the Oncological Drug Advisory Committee of FDA) spoke about eligibility and randomization issues.

Eligibility criteria defines the population being studied, protects the patients from risk, facilitates comparison across studies and minimizes interpatient variability (needs homogenous population); and must compensate for poor medical judgment where doctors may not be thinking carefully about a particular patient.

Ann’s NOTE: I do not believe that today’s busy oncology doctor can remember details about any particular patient, nor do they have time to reread the chart. About the only time a patient can go on study is if there disease has just recurred, or taken some other turn for the worse. In other words some flag gets raised for that patient at that time.

The requirements include the basics, such as: does the patient have the disease being studied?; is this treaetment safe?; does the patient and doctor agree that this is appropriate treatment?, etc.

Randomization is considered the best aspect a trial can offer. They call this the "gold standard". It is somewhat rare for trials to be masked (sometimes called blinded) in cancer studies. It may be useful when tumor/disease progression is the end point. That helps yield less ambiguous results. A placebo controlled study is also relatively uncommon in oncology-it is useful if there is a toxicity profile or quality of life issue to be discovered.

Dr. Schilsky also discussed the idea of equipoise, referring to a situation in which there is genuine uncertainty about which treatment will be most effective for an individual patient. A doctor will find it difficult to recommend randomization if s/he believes that one treatment is superior to another, or if the patient feels this way.

A randomized trial is not necessary to demonstrate a quantum leap in a group of patients with uniformly poor outcomes, it is most useful when the incremental benefit is less.

Some issues: doctors are uncomfortable admitting uncertainty, patients always want the best treatment, if there is a major difference in treatment there is the least equipoise and it is most difficult to randomize, there is often an inherent belief or tendency to feel that experimental treatment is better. Usually there is an option to receive the treatment off protocol.

There are alternatives to randomization which include a single arm as compared to historical controls but it is hard to ensure that one is comparing similar groups. There have been changes in general medical care, changes in staging procedures, there can be selective recruitment and difficulties of analysis reporting.

Ann’s NOTE: At the conference at Johns Hopkins a speaker from the UK stated that mortality rates dropped there as soon as a program was established teaching doctors that patients could survive a cancer diagnosis. There was no other identifiable contributing factors.

Trials have been tried with pre-consent randomization in which patients are told which arm they have already been accepted into. This may create a high drop out rate. A trial could also be designed that uses the new versus standard therapy if expectations were well known.

Cross-over is often a guarantee that patients will eventually get the newer treatment if their disease worsens. Of course that can obscure the study endpoints (this happened with the BCPT 1 when subjects receiving the placebo were randomized to receive either Tamoxifen or Raloxifene in the STAR trial. This meant that finding out survival information was rendered impossible.

Ann’s NOTE: I suggested to Dick that a way to enlarge the number of patients in a study would be to offer the other arm to those patients refusing the trial-in other words they would qualify for the control or standard therapy arm, and those patients who consented to take the new/experimental treatment could do so. There would be a difference in the mental attitudes but perhaps this would not impact the trial because there would probably not be unusual differences in the patient’s disease state.

He said this was one of the ideas under consideration to expand patient participation. I also suggested that patients who were horrified by the toxicity profile they have to read before signing an Informed Consent form be given a toxicity profile for the standard therapy they would get instead. Obviously any such profile on a cytotoxic (chemotherapy drug) would be rather horrendous.

It might have the effect of reducing the number of patients who agree to conventional treatment in situations in which it is obvious they would not get much benefit.

An Advocate's Perspective

Standards for testing/studies

When the Tumor is NOT the Target
Education/Utilization of Volunteer Pt Advocates:Clin Trials
Managing Conflicts of Interest in Conduct of Clinical Trials

JAMA, 1/02

UK:Paying Docs for Enrollment is Wrong
Funding Source a Strong Influence on Trials
Financial Conflicts in Clinical Trials
Natl Survey of Agreements:Medical Schools/Industry Sponsors
WHO Experts  New Rules/Clinical Res

Medscape, Pharmacotherapy, 2/02

Nontoxicity Endpoints Phase I: Targeted Non-cytotoxic Agents

JNCI, 7/04

Supporting 'Double-Blind Clinical Trials

Annals of Oncology, 3/02

Selective Reporting Biases: Cancer Prognostic Factor Studies

JNCI, 7/05

Very Critical of Clinical Trials-Part I

TIME Magazine,2002

TIME Magazine article -Part II
TIME Magazine Part III
Patient-Centered Approach:  Participatory Action Res Clin Trials

Integrative Cancer Therapies, 3/05

The Trust Factor: Editorial

The Oncologist, 4/02

Int'l Network & Developing Nations

Reuters Health,5/30/02 Ethical Review Standards

Unethical:Underpowered Trials

JAMA, 6/02

Clinical Trial Primer

LINK to Moffitt Ctr publication

Premature Termination/Clinical Trials (excerpts)

Medscape, 8/02

Media's & Human Subject Participation


Comparison Outcomes: In Trials versus Outside
Use of Federal Prisoners in Clinical Trials?
Patient Selection:Applicability of Results

British J of Cancer, 9/02

Hospice Versus Phase I
Patients' Decisions and Tamoxifen
Notifying Patients/Physicians:Clinical Trial Results
Valid and Informed Consent: Still an Issue
Instl Review Bds:Advocate Perspective

Sandra Batte

Clinical res/Exp treat 11/3/97

Insurance issues re clinical trials

HMO Disputes and State Programs
Pharmas Dictate What/How Research Published

NEJM, 10/02

Clinical Trial Registration:Statement Med Journal Editors
Public Attitudes on Participation

J Clin Onc, 2/03

Are Large Clinical Trials Ethical

Lancet, 2/03 Dr. David F. Horrobin

Coalitn of Natl Cancer Coop Groups

Improved Design for Clinical Trials & Multiple Agents

Abstract #B185 Frontiers in Cancer Prevention Res, 2003

Evaluation of Randomised Controlled Trials

By M.J. McKeown, MD, FACOG, FACS Thanks to

Missing Covariate Data w/in Cancer Prognostic Studies: Review
Contradicted & Initially Stronger Effects in Highly Cited Res

LINK to organization that runs the meetings

Placebo Research

J Alternative & Complementary Med, 10/04

The Placebo Effect - Seen on MRI
"Why Most Published Research Findings are False" Part I

Public Library of Science, 8/05

References Part I
Part III - "Why Research Findings Are False"
Part II - "Why Research Findings Are False"
Evidence-based Movement Exclusionary - Paper states

Int J Evidence-Based Healthcare, September, 2006

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