Objectionable Practices in Research Recruitment

Under construction 2005-02-28. We appreciate your patience.

News Stories and Press Releases

People often first learn about research in news stories, but news stories, however, unlike study advertising materials proper, are not reviewed or approved by an Institutional Review Board (IRB). Judging from the content of some of them, it often seems like investigators might take advantage of the lack of review and oversight, either to make claims that would be prohibited elsewhere, or to otherwise use media coverage as a sort of back door recruitment effort. In all cases, it's helpful to be able to sort out some of the wilder claims in news stories about research. What follow are examples of coverage that can mislead the unwary.

1. Misrepresenting research as medical treatment.   On 2005-06-27, the Hanover (PA) Evening Sun published an article titled Magnetic healing powers in which writer Melody Asper extolled the efficacy of an experimental medical device being investigated by Trent Nichols M.D., at the Advanced Magnetic Research Institute in Hanover, Pennsylvania. The article misrepresented research as medical treatment and contained a number of misstatements, misleading statements, and left out important information. On 2005-02-24 FDA took administrative action against Dr. Nichols for a number of violations of FDA regulations for the protection of human subjects in research. Specifically, FDA objected that Dr. Nichols had failed to obtain adequate informed consent, failed to follow the investigational plan, applicable FDA regulations or conditions required by the IRB, and failed to maintain adequate records. While it's true that Dr. Nichols responded to the FDA warning letter and agreed to correct violations, it's also true that, all things being equal, your first choice should not be a study conducted by an investigator who has received an FDA warning letter for his failure to protect the rights and welfare of research subjects.

According to the Hanover Evening Sun article:

Max began his first sessions in April and soon will conclude nearly 450 hours of treatments for as long as 20 hours at a time.

Comment: Max is a research subject in a clinical trial testing a medical device for safety and efficacy in a number of diseases; while the research protocol apparently includes at least 450 sessions in which Max is exposed to the experimental device, these sessions are not "treatment". It's important to remember research and medical treatment are not the same thing.

MME treatments still do not have FDA approval, but Nichols' work is part of a study being conducted by the Institutional Review Board.

Comment: This statement is ridiculous and incorrect. The study in which Max is a subject is not being conducted by the Institutional Review Board (IRB) because an IRB does not conduct studies. A person who suggests studies are conducted by an IRB is clueless. Avoid studies associated with these absurd claims like the plague. An IRB is a group of men and women with appropriate training and experience who's primary purpose is to protect the rights and welfare of research subjects. The IRB does this by reviewing and approving proposed studies to make sure risk to subjects is minimized and informed consent is obtained prior to enrollment, among other things. In Max's case, because the research is subject to FDA regulation of research conducted under an Investigational Device Exemption (IDE), the IRB is also subject to FDA regulation at 21 CFR 50, 56, and 812.

A study is conducted by an investigator or principal investigator.

In this way, Nichols and other researchers are able to treat patients and then submit their data to the FDA, which is continuing to evaluate MME treatments.

Comment: Nichols and other researchers are not treating patients; Nichols and other researchers are testing an experimental medical device on research subjects. When the investigator is also the sponsor of the study, special procedures are necessary to mitigate conflict of interest, and prudent sponsors often hire contract research organizations to conduct their studies to avoid precisely these difficulties. The consent form should disclose the financial interest (if any) of the investigator.

FDA is not continuing to evaluate MME treatments because FDA does not evaluate treatments. The manufacturer or sponsor has filed an IDE with FDA to conduct studies; with the exception of unanticipated serious adverse events, deaths, annual reports, and reports of failure to comply with applicable regulations, FDA does no evaluation. In any case, the agency cannot evaluate a study until it is concluded. When the study or studies are complete, the sponsor of the IDE (the device manufacturer) will (ostensibly) file an application with FDA to market his medical device to treat the indications supported by this and other research. Only after receiving this application will FDA begin its evaluation the device's safety and efficacy for the specified indications.

Nichols said that all the studies being done have shown no adverse side effects except for an occasional temporary headache, dizziness or nausea. Also, treatments have never been shown to make any existing problems worse.

Comment: Adverse side effects is an oxymoron. A side effect is an unintended effect, neither good nor bad - just unintended. Medical device manufacturers and IDE sponsors are required to collect and report medical device adverse events and serious medical device adverse events to FDA. By definition, an adverse event is a noxious (harmful) reaction which may or may not be caused by a medical device (or drug). Investigators are required to record all adverse events and assess whether or not they were caused by the experimental device.

Most people don't realize that adverse events include elective surgery, car accidents, unrelated illness, injury, and accidents ranging from decapitation to stubbed toes - happening while a subject is enrolled in the study. There are literally thousands of adverse events reported in every study, but only some will be caused by the experimental device or drug. Because the definition of an adverse event is so broad, we should be extremely skeptical when investigators claim there are no adverse events, no risk of adverse events, or very few adverse events all of which are transient and not serious.

Nichols' wife and institute co-owner Sharon Nichols said the only downside she can see is that the treatments aren't covered by insurance because they aren't fully recognized by the FDA. That means that the $50 per hour must be paid by the patient's families or through community support.

Comment: The experimental medical device is being tested on Max to see if it is safe and effective for the treatment of cerebral palsy, or so the article appears to say. While it's true that insurance companies may refuse to pay for certain interventions they judge to be experimental or ineffective, many insurance companies provide coverage for beneficiaries enrolled in research. Several states require coverage in certain situations (cancer) and Medicare pays for FDA IDE studies, so-called Category B medical device studies, FDA IND drug studies, and studies sponsored by NIH.

People should be aware of FDA regulations pertaining to charging subjects in studies testing medical devices:

The Investigational Device Exemption (IDE) regulations allow sponsors to charge for an investigational device, however, the charge should not exceed an amount necessary to recover the costs of manufacture, research, development, and handling of the investigational device [21 CFR 812.7(b)]. A sponsor justifies the proposed charges for the device in the IDE application, states the amount to be charged, and explains why the charge does not constitute commercialization [21 CFR 812.20(b)(8)]. FDA generally allows sponsors to charge investigators for investigational devices, and this cost usually is passed on to the subjects.

Source: http://www.fda.gov/oc/ohrt/irbs/toc4.html#products

No treatment is recognized by FDA either partly, fully, or any other way because FDA does not regulate treatments. FDA regulates medical devices (and drugs, etc.) in interstate commerce. Medical devices are approved by FDA through one of several routes (510(k), PMA, or HDE); some approvals may be conditional (with required post-approval studies, for example), but no approval is partial.

What is needed right now is a lot of additional funding so that more people that need it can benefit from the MME, said Sharon Nichols. There are so many children out there like Max who could be helped.

Comment: People considering enrolling in research should be wary when the study sponsor appears to have financial problems. It's the exception rather than the rule that subjects are charged in research, and quite obviously the sponsor must have adequate funds set aside to complete the study and data analysis. If the sponsor is unsure that he can complete the study, it's probably unethical to continue to enroll subjects. At minimum, people should ascertain in writing that the investigator has clinical trial insurance in the amount of at least $250,000/$1,000,000 – and remember that this is a specific insurance product in addition to medical malpractice insurance carried by physicians – malpractice insurance does not cover claims for injuries and damages in research.

Accessed 2005-08-17 at: http://www.eveningsun.com/Stories/0,1413,140~9954~2940963,00.html

An Arizona reporter described several similar objectionable conditions at the study site in Tucson, and subsequently requested information from FDA. Magnetic treatment clinic draws controversy. Carla McClain. Arizona Daily Star. 2005-05-09. Available from http://www.dailystar.com/dailystar/dailystar/74186.php

Where to find more information:

• Information about adverse event reporting in research is available on the FDA web site at: http://www.fda.gov/cder/guidance/iche2a.pdf
• To get information or complain about studies conducted under FDA Investigational Device Exemption (IDE), see: http://www.fda.gov/cder/Offices/DSI/contact.htm

2. Species Bait and Switch.   This press release sounds great doesn't it?

Whole-body hyperthermia and metronomic chemotherapy prevent cancer metastasis.

According to a study from the United States, many women diagnosed with invasive breast cancer have undetected occult metastases at the time of their primary tumor diagnosis. The development and growth of these micro-metastases relies heavily on angiogenesis. Therefore, administering an angiogenesis-blocking treatment from the time of diagnosis could reduce the incidence of metastasis and, ultimately, increase patient survival.

Comment: Look again: we've been had by rhetoricians masquerading as copywriters. Then we see the actual study pertains to rats.

It is hypothesized that an intangibleness strategy combining fever-range whole-body hyperthermia (FR-WBH) and metronomic chemotherapy could inhibit the development of metastatic disease with minimal toxicity. To test this theory, a low, daily dose of the topoisomerase I inhibitor irinotecan hydrochloride (CPT-11) was administered over a prolonged period of time to rats bearing the highly metastatic MTLn3 mammary adenocarcinoma primary tumor surgically excised on day 12 after implantation, described K. Sumiyoshi and coauthors, University of Texas, Houston Medical School.
Accessed 2005-08-09 at: http://www.obgyn.net/newsheadlines/womens_health-Breast_Cancer_Therapy-20030408-16.asp

Comment: Disseminating misleading information like this is inexcusable; considering the targeted audience is likely to consist of people with advanced cancer, it's egregious. What's worse, the deception is deliberately calculated to make you believe something that you might not believe under different circumstances. The opening paragraph offers two statements: 1) that many women with invasive breast cancer also have undetected (tiny) metastases at the time of initial diagnosis, and 2) tiny metastases depend on angiogenesis (creation of new blood vessels) to become bigger metastases. OK, but what does this mean to me? According to the writer, the answer is obvious: intervention to prevent angiogenesis administered when you're first diagnosed would logically prevent or reduce angiogenesis, which in turn should prevent tiny metastases from becoming larger. On casual inspection this sounds perfectly logical, but it might or might not be useful to prolong your life if you died from growth of the primary cancer or the intervention to inhibit angiogenesis proved toxic. But it gets worse: these statements, even if accurate, pertain to women. The second paragraph goes on to describe an investigational treatment to inhibit angiogenesis which researchers tested in rats. We eventually discover the bold statement that Whole-body hyperthermia and metronomic chemotherapy prevent cancer metastasis is in fact a series of assumptions applied to an experimental intervention in rats held out as a promising treatment for humans.

Oncologists, more than any others, understand the desperation patients with advanced cancer often experience. When you come across overblown or misleading articles like this, you may wish to factor this into to your decision to enroll in research conducted by its source. Either choose another study or ask for clarification.

Study Advertisements

While they don't promote the safety and efficacy of the investigational drug, device, or dietary supplement, some study ads nevertheless contain information that's inaccurate, misleading, or obscure. The Alista ™ Clinical Study Fact Sheet (number 3, below) is a relatively tame example of the sort of information potential research subjects are bombarded with.

1. Mistletoe Extract and Gemcitabine for the Treatment of Solid Tumor Cancers. Available from http://www.clinicaltrials.gov/ct/show/NCT00044161?order=5. Accessed on 2005-11-24.

The study listing provides the following false and misleading information to vulnerable patients with advanced refractory cancer:

The FDA has approved mistletoe extract for use in cancer treatment studies. Mistletoe extract has been used either alone or together with conventional anti-cancer drugs to treat cancer in tens of thousands of patients in Europe.

The statement that FDA has approved mistletoe extract for use in cancer treatment studies is false because FDA doesn't approve drug studies. In fact FDA warns investigators not to make this claim in the Guidance for IRBs and Clinical Investigators — 1998 Update, Guide to Informed Consent. The fact that mistletoe has been used by tens of thousands of patients in Europe is misleading because it encourages readers to believe mistletoe might be safe and effective for their condition, but wide use does not equal safety or efficacy, and mistletoe may or may not be safe or effective when administered with Gemcitabine in this study. Providing false information to induce subjects to enroll in research is unethical and reprehensible.

2. A Phase 2 Study of the Safety and Efficacy of a Novel Anti-Inflammatory Investigational Drug in Adult Asthmatics. Available from http://www.clinicaltrials.gov/ct/show/NCT00150397?order=9. Accessed on 2005-11-24.

A few sponsors don't include the name of the drug being tested. For example, the Pfizer study titled A Phase 2 Study of the Safety and Efficacy of a Novel Anti-Inflammatory Investigational Drug in Adult Asthmatics is testing an investigational drug named Investigational Study Drug. The real problem with ClinicalTrials.gov is that not all sponsors who are required to register studies are doing so. The most recent survey by FDA in August, 2005 found that only 35% of industry-sponsored studies that were required to register were actually registered. This suggests widespread ignorance or non-compliance, and it's especially difficult to understand in view of industry's continual lamentation about how difficult it is to recruit study subjects. (1)

3. Alista ™ Clinical Study Fact Sheet. Available from http://www.entdocs.org/Clinical_Trials_Fact_Sheet.pdf. Accessed on 2006-03-02.

Comment: (General) The fact sheet has a section titled What is the benefit of participating in this trial but no section describing the risk of participating. This is unbalanced and misleading because potential subjects might conclude there is no risk.

A clinical study is a research method used to test a drug or medical device in humans after it has demonstrated a positive result in the laboratory and/or in animal studies.

Comment: This is misleading and incorrect because it implies that a positive result in pre-clinical testing invariably precedes human studies. First of all, much of pre-clinical testing aims to rule out a number of problematic effects, so the last thing researchers want is a positive test result. For example, a positive result from the Ames Test means the experimental compound is a mutagen, from which researchers conclude it's also likely to be a carcinogen. A more practical example is the recent FDA withdrawal of Palladone ™: when the sponsor learned the drug's time-release coating rapidly dissolved when dropped in a beaker of ethanol (alcohol), it sponsored two human studies: in one study, subjects were given various concentrations of alcohol along with Palladone ™; in the other study, subjects were given a standardized concentration of alcohol at various intervals before and after being dosed with Palladone ™. When these studies confirmed that alcohol could indeed cause the full dose of the drug to be immediately released into subjects' bloodstream, the drug was subsequently voluntarily withdrawn from the market. For more information, see the FDA press release of 2005-07-13: http://www.fda.gov/bbs/topics/NEWS/2005/NEW01205.html.

A clinical study uses the principles of the scientific method to answer a question under controlled conditions.

The U.S. Food and Drug Administration (FDA), which oversees human drug testing to protect the public, closely monitors studies.

Comment: This statement is incorrect: FDA does not monitor studies while they're underway. The agency selects a small number of study sites to audit prior to approving an application to market a new drug or device. The primary purpose of these audit inspections is to assess the quality and integrity of the data submitted by the applicant. By sampling case report forms and medical charts, the agency satisfies itself that the patients are real (versus made up) and that each signed a consent form. Since these pre-approval audits can take place months, or even years after a study has ended, they have absolutely no effect on manner in which the study was conducted or the safety of the subjects enrolled in it. To be fair, however, on rare occasions FDA may receive information suggesting such severe and eminent harm to subjects that it warrants inspection on an expedited or emergency basis. Neither pre-approval inspections nor for-cause inspections constitutes anything like monitoring, a term which most people would suppose meant that FDA knew exactly what was happening in every study and at every trial site in the U.S.

The goal of each study is to answer scientific questions and to find better ways to prevent, diagnose and treat disease.

Comment: If only they'd ended the sentence after the word and … The purpose of a study is to answer a question. Period. The questions answered a study are not limited to those intended to lead to improvements in prevention, diagnosis, and treatment of disease, and not every study aims to find better treatment. Bluntly speaking, to obtain an FDA marketing license for a new drug, a sponsor simply needs to demonstrate that the drug does what it claims on the label with evidence from adequate well-controlled trials. The sponsor does not need to demonstrate the drug is better than a currently marketed drug. In fact, many drugs treat the same disease or symptom and are equally effective. This leads some people to accuse the drug industry of profiteering from the development of so-called me too drugs. Since these drugs treat the same disease or symptom as one or more marketed drugs, people often wonder why another drug is needed. While it may be true that different drugs have similar safety and efficacy, it's also true that different drugs have different effects in different people. The most effective drug is ineffective in patients who cannot tolerate it. This is not to say, however, that the drug industry isn't making scads of money — it is.

Any institution conducting research involving human subjects is required by federal regulations to have IRB review and approval of the research activity

Comment: This statement is incorrect. Research with federal funding must be reviewed and approved by an IRB as set forth in Common Rule (45 CFR 46), and studies testing products subject to FDA IND or IDE regulations (21 CFR 312 and 21 CFR 813) must obtain IRB review and approval as set forth in 21 CFR 56. This does not include all research on FDA-regulated products and it does not include all research conducted at hospitals, clinics or elsewhere. As implausible as it is, not all research in the U.S. is regulated. If fact, this is why CIRCARE exists.

If participants experience unexpected/severe side effects or if evidence exists that the patient risks are outweighing the benefits, the trial will be stopped and no one else will receive the medication

Comment: This quote, like the one above, comes from a section titled Institutional Review Board (IRB) and Study Participant Protection, and aims to inform potential subjects how an IRB protects research subjects, apparently to reassure them. Unfortunately it not only gets the circumstances in which IRB review and approval are required wrong (above), it also misstates what an IRB can do and what it's likely to do. When a subject experiences a unanticipated serious adverse event (SAE), how, when, and to whom this gets reported depends upon several things, including but not limited to funding source, study location, institutional affiliation of the investigator, willingness of investigator and sponsor to comply with regulations, and whether IRB review and approval is local or centralized. The biggest problem with this statement is that it implies an IRB has the authority to terminate a study. It doesn't. Only the sponsor can terminate a study. It's true that in extreme situations an IRB can withdraw approval of a study, in reality these situations are extremely rare, and associated with events such as imprisonment of the principal investigator or suspension of the principal investigator's medical license. When an IRB receives reports of unanticipated SAEs that make the ratio of risk to benefit significantly different from when the study was initially reviewed and approved, the IRB most often will require modification of the study, specifically in how much drug is given, how often, and to whom. When subjects experience unanticipated SAEs, the sponsor and investigator try to figure out why. If it turns out that the SAE happens to subjects who share some similar quality, those subjects are removed and study continues. Study termination is rare.

The Alista ™ Fact Sheet deserves credit for what it did not do: it didn't claim the drug would work, and considering the fact that they're testing a drug to improve female sexual arousal, the possibilities for hype are limitless.

Free Money

To be posted.

top

Notes

1. FDAMA Section 113: Status Report on Implementation. Available at:   http://www.fda.gov/oashi/clinicaltrials/section113/113report/default.htm. August, 2005.

Last Updated: 2006-03-02

If you find the information on this page helpful, please support CIRCARE with a tax-deductible contribution today. Help us advocate for meaningful protection of human subjects in research. Donating on-line with PayPal is quick and easy. Find out more on our Support page.

---