Your life and health depend on the content and conduct of a trial and your response (or lack thereof) to the trial agent(s) --- in my opinion, a patient’s maximum due diligence is required before entering a trial because you are your only advocate in this setting. Below I propose a summary check list of those questions we should ask ourselves before signing a consent form to participate in a clinical trial:

1. What is the purpose of the trial -- to treat the disease, or is it a medical experiment?

2. What phase is the trial? The earlier the phase, the more experimental.

3. What are the risks?  What are the rewards?  List all potential side-effects.

4. Are other doctors/institutions participating in the trial protocol?  Demand a synopsis of the results to-date in any other arms of the trial.

5. What happens if there are problems or ill effects?  Who is responsible and who pays?

6. What are the qualifications of the principle investigator?  Is he/she trained in the scientific method of conducting experiments?

7. Demand a complete written financial disclosure of all investigators/institutions.

8. Insist that a third party who is familiar with drugs, scientific methods of experiments, and medical protocols review the consent form with you.

What is a clinical trial? Research studies to answer scientific questions re prevent, diagnose, or treat cancer; the trials can be for new agents addressing specific cancers, or combinations of new agents + conventional agents, or new combinations/dosing/scheduling of conventional agents.

Types of clinical trials--a) new treatment approaches, b) prevention trials; for agents/supplements applicable to people who have never had cancer, or to prevent recurrence, c) screening trials to discover cancer in its early stages, d) supportive care trials.

How clinical trials are supposed to work: 1) basic research = a hypothesis re why a new agent/procedure might be effective, 2) animal studies, 3) proposal to a review board for approval, 4) recruit patients, 5) inform patients by detailing all potential risks/benefits = signing a consent form, which is a complicated legal document that can be 30 pages long, 6) PH I = safety study, dosing and scheduling; a few patients; about 70% of such studies make it to the next phase, 7) PH II studies; usually a few hundred patients; a control group is added to see if the experiment is having effect, 8) PH III; usually involves thousands of patients; usually compares the experiment to existing/conventional treatments and a placebo, 9) FDA approval, 10) PH IV; if the drug/protocol is approved, the applicant must report up to 10 years any unexpected reactions.

Summary

Medical research has expanded significantly in recent years and large clinical drug trials with human subjects are necessary to accelerate the process of getting the drugs to market and into clinical practice. But in the rush to attain large cohorts of patients enrolled for an expanding number of experimental drugs, many of the duties of research scientists have been transferred to clinical practitioners. The roles of research scientists and clinical practitioners differ significantly but are often blurred when considered from the viewpoint of the patients. This blur becomes more opaque as the academic/science research is increasingly influenced by commerce/finances. The burden of assuring high ethical standards and societal trust in these experiments is falling more on the patient to be vigilant in assuring that we are not just a sacrificed means to a financial end.

When recruited for a trial, we must become intimately familiar with the goals of the experiment and realize that they inevitably differ considerably from clinical care for our disease. We must assure that we understand the Consent Form and receive full disclosure of the financial aspects of our participation in the experiment. We must demand that the experiment investigators reveal their remuneration for having recruited us, as well as the details of their relationship with the drug companies and institutions sponsoring the experiment. Moreover it is incumbent on us, as participants in the experiment, to assure that the doctor/investigator is qualified in both the medical practice of the protocol, as well as being qualified as a research scientist; and that the program follows all aspects of research ethics and scientific methods.

Rest assured that you have the responsibility to fully understand the nature of the experiment and whether it might be beneficial for you; and also that the doctor who recruited you for the experiment is fully qualified as a research scientist in addition to being a clinical practitioner.

Two decades ago all clinical trials were performed in academic centers and fourteen years was required on average for a new cancer drug to develop from pre-clinical to Phase III human trials.

Much of the tectonic shift in clinical trials of the past few years is driven by the relationship between medical scientific research by drug companies and institutions and their need to accelerate drug development by recruiting large cohorts of patients for experiments. The natural needed expansion of efforts is to recruit our doctors to recruit us as experimental models and today 65-70% of clinical trial accruals originate from community hospitals. To provide this service to cancer science, our doctors receive considerable financial remuneration from drug companies and government agencies, both as a per-head recruitment fee (up to $6,000 per patient recruited), as well as bonuses and administrative costs.

Obviously this creates a conflict between clinical care and compensated research by a practicing doctor who is seldom trained in even the basics of proper scientific research methods; and community oncologists have no guidelines which serve in the approach to patients for participation in a scientific experiment. However, it is recognized that our community doctors have immediate access to the large cohorts of patients needed for the experiments. Notwithstanding the contracted time frame to rush drugs to human trials/market by utilizing community patient pools/doctors, only 3% of cancer patients participate in clinical trials.

Why are patients reluctant to enter trials? Some patients fear that the trials are to satisfy the need to publish, or financially reward the doctor/institution vs. trying to advance the medical science of cancer treatment. Some patients fear the placebo of randomized trials or a perception that they had rather seek standard treatments rather than experiments. Many patients are reluctant because their insurance refuses coverage for the experiment, or any adverse ramifications thereof. Other patients are reluctant to do the required ‘cleansing’ required for trial entry. (4) Also, many reports reflect that the patients who do enter trials are unclear about the objectives of the trial. Less than 5% of the patients in a PH I trial will receive any benefit; yet 85% of those patients stated their reason for entering the trial as expecting therapeutic benefit. (6) Do you agree that before entering a trial and signing the consent form, the burden is ours to perform the maximum due diligence in order to know every aspect of a trial and our exact expectations there from?

The professional and legal fiduciary duties of research scientists and medical practitioners are significantly different, as well as their formal academic training: research scientists generate knowledge that might result in drugs/agents that provide clinical therapeutic benefit; our practicing doctors are morally and legally required to focus on our health and welfare. To have our doctors fulfilling both duties simultaneously can certainly present a conflict of interests and can result in divergent objectives that are to our detriment.

Recent dynamic trend changes affecting clinical trials:  R&D investment by the top 20 drug companies has doubled in the past 7 years--revenues are forecast to grow only 7%/year in the coming years...they must generate $25 billion additional annual sales to maintain current levels of profitability...this requires launching 24 to 34 new drugs per year that cost less to develop or sell at higher prices to maintain profitability... (1)

Academic/institutional centers are slowed by lengthy review processes and large overhead expenses. Thus, the requirement for less costly and time-consuming venues, i.e., contracting to community-based practicing doctors for patient recruitment and experiments is faster, economic, and provides broad recruitment possibilities...the number of practicing doctors likewise conducting clinical research has increased 600% in 10 years...research in academic/institutional centers has decreased 80% in the past 10 years and shifted to medical practitioners...funding to community-based trials has increased 3-fold in the same time frame. (1) More than 80,000 clinical trials were conducted in the U.S. on 2001. (6)

This transfer of research efforts is accomplished by private organizations who advertise and recruit community hospitals and doctors for their access to the community’s patients. These private organizations are paid by the drug companies; their continued existence is dependent on positive trial results; and the financial viability of the entire chain of funding for the experiment could possibly be compromised by this conflict of financing/profit vs. research integrity and safety of patients participating in the experiment.

While most of the private organizations that recruit and conduct research in a community-based setting are subject to FDA regulation, they often contract to local private review boards for oversight of the projects and these second-tier organizations are not subject to FDA oversight. These secondary organizations are for-profit and their very existence depends on continuous flows of projects to review and thus, another conflict is created as they have the opportunity to use much less stringent review standards.

In 1999 two news articles (10, 11) revealed the result of some of these conflicts and patients were described as "...commodities, bought, sold, and traded by testing companies and doctors." They further revealed that recruiting doctors not even involved in the trial were paid to simply refer patients to the investigator. In some trials, finder’s fees and bonuses for reaching quotas amounted to several thousand dollars/patient. (1) This cascade of recruitment and financing removes the activity from governmental oversight and certainly can result in conflicts of interest that are not in our favor; in fact, it can make us irrelevant in the process, except as a commodity. Several recent clinical trials were suspended (some at prestigious institutions) for breaches of ethical standards, some of which resulted in patients’ deaths.

But, any oversight of the entirety of clinical trials is lost in the myriad of rules, regulations, and non-related government entities. The many government agencies that sponsor research rely on trust that the system will be followed and do not routinely audit programs. Each agency has its own rules and regulations: the NIH; the Office of Management Assessment which must refer violations to the Office of the Inspector General (OIG), which refers them to the Justice Department, who rely on the federal False Claims Act (FCA) for compliance guidelines. For Federally funded research, recipients thereof must agree to disclose ‘significant’ financial interests, establish review procedures for conflict of interests, create proper informed consent forms, and annual certification that the rules and regulations are being followed. But, there is nobody to review or assure compliance with these rules/regulations.

Moreover, once the projects are delegated to private organizations for funding and recruitment of investigators and patients, the research is subject to a completely different set of rules and oversight/review enters a new maze of different regulatory agencies and regulations, but all of these are considered to be in the sphere of the maze of the first agencies/regulations. All of these oversight/review agencies now say that given the increased commercialization of research and the vastly increased number of multicenter trials, an inordinate increase in workload has resulted and therefore, only minimal, sporadic review is possible.

Specifically, the job of the Office for Human Research Protection (OHRP)* is to oversee and monitor clinical trials. In 2001, OHRP had only two full-time investigators to monitor more than 4,000 federally funded research institutions; and each institution has numerous clinical trials in progress. Since 1980 the agency has audited, on average, just four sites per year. During the same time frame, the FDA made 200 site visits to the approximately 1,900 sites that oversee research on FDA-regulated products. (6)

If by chance a possible financial violation is discovered, then the Federal Anti-Kickback statute is relied upon. This generic arcane statute makes it a felony to accept financial incentives from commercial entities (drug companies), or paying trial participants, or paying for the referral of patients covered by Medicare/Medicaid.

Of the 80,000 clinical trials conducted in 2001, a quarter of them received no federal oversight whatsoever; and where oversight is mandatory it is applied loosely (if at all) due to the vast numbers of trials and multi-center locations. (6) I suggest that in no way are we protected by any of the myriad conflicting rules and regulations governing clinical trials and the system is free to conduct the trials in any manner they so desire. As we are recruited for trials, we will be very fortunate if we select and are accepted in one that is being conducted in our best interest.

1) Study the vast array of agents in trials and understand the generic classification thereof. Is it a vaccine?---Biological Response Modifier?---Signal Transduction Inhibitor (there are 300+ in development)?---Monoclonal Antibody (what is its purpose?; is it labeled with a treatment agent)?---Is the trial agent in conjunction with a treatment agent (chemo/RT)?---etc.

2) What is the cleansing requirement?---most trials require us to be ‘clean’ of treatments at least 30 days before trial initiation and during the trial---can you afford to be ‘clean’ without your cancer rapidly proliferating?

3) What previous treatments deny trial participation?---often, previous chemotherapy, EBRT, or radioisotopes deny trial entry.

4) What disease conditions deny trial participation (bone mets/soft tissue disease, PSA rise/decline)?

5) What happens if you react negatively to the trial agent(s)?---are you summarily dismissed (often, you are dismissed and not even considered as a statistic = you never existed as a participant)?

6) Does the protocol provide for funding of medical care arising from complications associated with the research? What medical care can you expect if you are dismissed for adverse reactions to the trial agent(s) (most consent forms say you are on your own and often, your primary doctor does not have the vaguest idea what to do with you once you have the trial agent(s) in your body)?---Assure that your insurance coverage will respond to any treatments required as a result of the trial agent(s); (many insurance plans deny reimbursement for damage from experimental drugs).

7) Assure that the doctor/investigator who recruits you for a clinical trial is qualified in the practice of medicine specific to the trial.

8) Assure that the doctor/investigator has adequate training in the conduct and ethics of research methods and have him/her satisfy you that the research project protocol and proposed procedure conforms to government regulations.

9) If the recruiting doctor/investigator is also your treating/consulting doctor, assure that a third person (who is not financially involved) reviews the consent form and explains it fully to you before you sign it.

10) Insist that the recruiting doctor/investigator reveals all financial relationships with all parties and commits to the exact financial remuneration for recruitment and the chain of financial relationships with government agencies, drug companies, and private contract research organizations.

This proposed check list seems onerous---but your life depends on your own due diligence in assuring that you understand what to expect from participating in a clinical trial.

NOTE: I am not a doctor and can not render medical advice. I am not a medical researcher. I am a prostate cancer patient and I performed this layman’s analysis for my own decision-making purposes. In conjunction with a medical team, every cancer patient must make their own decisions regarding treatment options. I make no claim that this analysis is definitive or complete. I invite any and all additive contributions to my analysis that will provide patients a framework which will enhance their ability to make informed decisions regarding possible entry into cancer clinical trials.

* The Office for Human Research Protection (OHRP) is a result of: the national research Act of 1974 required institutional review boards to approve and monitor all federally funded research; the Department of Health and Human Services complied by creating the OHRP.