Clinicaltrials.gov Mission At Risk From Proliferating For-Profit Trials

It’s hard to even imagine the world of investigative medicine without the wonderful resource of Clinicaltrials.gov, the global hub for clinical trial listings. I recently interviewed the Director of Clinicaltrials.gov, Dr. Deborah Zarin here, which is a fascinating read.

As great as Clinicaltrials.gov is as a resource, unfortunately it faces a new, rapidly growing problem that is a serious threat to the site.

The Clinicaltrials.gov database is including a rapidly increasing number of for-profit clinical trials that are not by any stretch of the imagination traditional clinical trials. At present, the Clinicaltrials.gov rules largely allow any trial submitted to be listed in the database based on an honor system approach.

Dubious stem cell clinics are taking advantage of this loophole to get an air of legitimacy and often use their listing in Clinicaltrials.gov as a marketing tool to convince their potential customers that their trials are approved by the federal government (see hypothetical example below of such a web marketing approach), which at best is misleading.

Another level of strangeness to this situation is that although Clinicaltrials.gov is intended primarily to be a database for trials of experimental new drugs (keep in mind that stem cells products often are biological drugs), the dubious clinics–despite listing their “trials” on the site–claim that their stem cell products are not drugs.

As a result of this overall dubious stem cell trial problem, I believe that the Clinicaltrials.gov vetting system approach is in need of a major overhaul as soon as possible.

slickstem

How a for-profit trial differs from a regular clinical trial.

A traditional clinical trial is intended to evaluate new drug products for safety and efficacy, not to directly make the sponsor of the drug cash. If investigational drugs are proven both safe and effective, their use may go on to generate income and even a profit for a biotech company in the future, but the traditional trial is about evaluating the drug rather than directly raking in cash.

In contrast, a for-profit stem cell clinical trial today is a new breed. Such a trial itself is designed to directly generate a big profit for those running it. The profit from such trials comes not in the future should the drug be proven safe and effective, but rather right now regardless of whether the drug is any good or not.

So for these trials, a stem cell product, for example, could be unsafe and/or ineffective (and the trial sponsors may already even know that) and the stem cell clinic still potentially gets mounds of cash upfront. We are talking big profits as well, potentially in the tens of millions of dollars just from the clinical trial itself, again regardless of whether the product in question is safe or effective.

Vulnerable patients must pay to participate in such for-profit trials and they pay a premium so that the folks running the trial get what can often turn out to be a hefty profit. By and large, if you as a patient do not pay this hefty sticker price then your odds of getting to be in the trial are very low. Usually, you are out of luck.

Does Clinicaltrials.gov really want to list such trials in its database and in so doing be linked to, even if indirectly and unintentionally, the exploitation of vulnerable patients?

I doubt it.

So what can be done?

Clinicaltrials.gov needs to make some changes and do so now rather than later. I’ve explained my concerns to them and pointed out how they are being used by these stem cell clinics. I don’t know if they will listen to me or even if they agree with me whether they can overcome bureaucratic hurdles in the way of change to do something about this any time soon. Here are the key kinds of changes that are needed.

  • 1. Competing interest declaration. At the very least, if a company is directly profiting from a trial itself then that competing interest should be prominently displayed in the Clinicaltrials.gov listing. Patients have a right to know.
  • 2. No use of Clinicaltrials.gov listings as marketing tools. Clinicaltrials.gov should also have a policy about for-profits using the listing as a marketing tool on the company website. If dubious stem cell clinics, for example, convince patients to pay via website promotional material indicating that they are legit because their trial is listed on Clinicaltrials.gov, the listing should be deleted.
  • 3. Keeping the FDA informed about new trials. Clinicaltrials.gov should provide information on all new trials to the FDA and the FDA should examine whether they need to investigate these new trials for compliance. This kind of interagency cooperation makes perfect sense, but will it happen?

If no changes are made at Clinicaltrials.gov to deal with this problem any time soon, at some point the database overall could be damaged. I hope that doesn’t happen as I am a big fan of Clinicaltrials.gov.

Behind the scenes at Clinicaltrials.gov with Director Deborah Zarin

Deborah ZarinThis post is the first in a series about the Clinicaltrials.gov website.

This piece is an interview the Director, Dr. Deborah Zarin. I want to thank her for taking the time to answer my questions.

Later, I will post Part 2 in which I discuss my concerns about the trend of for-profit stem cell clinic trials being listed on Clinicaltrials.gov that in my view are not conventional trials.

First a little background on Clinicaltrials.gov before I get into the interview.

It is the global clinical trials website with tons of info for anyone interested in clinical trials ranging from patients to doctors to researchers and the list goes on and on. The bonus is its simple, yet powerful search tool, which works go find the specific info that you need.

clinicaltrials.govIn the crazy, exciting, disturbing world of clinical investigative and innovative drug development, Clinicaltrials.gov stands out as a way to learn and make sense of this dizzying arena.

The NIH and NLM maintain clinicaltrials.gov as a website on which clinical trial information can be deposited and accessed by principal investigators of the trials, patients, researchers, and others. It’s amazing.

Here’s the interview with some intriguing insights and information from Dr. Zarin.

1. What is the purpose and mission and Clinicaltrials.gov?

ClinicalTrials.gov provides the public with comprehensive information about nearly 175,000 registered interventional and observational clinical research studies – conducted in the US and worldwide. Of these, summary results are posted for nearly 14,400 records, many of which have not been published elsewhere. ClinicalTrials.gov is the largest publicly accessible registry and results database globally and receives over 112 million page views per month and 57,000 unique visitors daily. (See Trends, Charts, and Maps at http://clinicaltrials.gov/ct2/resources/trends.) Data are submitted to ClinicalTrials.gov through a Web-based Protocol Registration and Results System (PRS) by sponsors and investigators.

ClinicalTrials.gov was established by the National Library of Medicine (NLM) in 2000 in response to the Food and Drug Administration Modernization Act of 1997 and to support NLM’s mission of disseminating biomedical knowledge and advancing public health. Since that time, ClinicalTrials.gov has expanded significantly to support other international registration policies such as the International Committee of Medical Journal Editors (ICMJE) policy requiring prospective trial registration as a condition of publication. Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA 801) expanded mandatory registration requirements under previous Federal law to include non-phase 1 trials of FDA-regulated drugs, biologics, and devices, and additional information describing each study. FDAAA 801 also established a results database. (See History, Policies, and Laws at http://clinicaltrials.gov/ct2/about-site/history and FDAAA 801 Requirements at http://clinicaltrials.gov/ct2/manage-recs/fdaaa.)

The continued growth in the use of ClinicalTrials.gov can be attributed to U.S. Federal law as well as international recognition of the scientific and ethical importance of registration and results reporting. The combined registry and results database provides access to critical information about ongoing and completed clinical research for patients, healthcare providers, and policy decision makers. For example, potential study participants, clinicians, and researchers can identify trials of interest, examine summary protocol and recruitment information for ongoing trials and summary results information for completed trials. Journal editors, peer-reviewers, and readers could use ClinicalTrials.gov to examine the prespecified outcome measures and look at the summary protocol information for changes not described in submitted manuscripts and publications. Systematic reviewers could search for unpublished trials and results. An unanticipated outcome has been the use of ClinicalTrials.gov data to provide a window into the “clinical research enterprise.”

2. Are there certain trials that must be submitted by the PIs to Clinicaltrials.gov?

In the United States, two of the most relevant requirements are FDAAA 801 and International Committee of Medical Journal Editors (ICMJE) trial registration policy. FDAAA 801, a US Federal law, includes a legal mandate for a study sponsor (or its designated PI) to register and report results for certain non-phase 1 interventional studies of FDA-regulated drugs or devices. There are substantial penalties for non-compliance. Rulemaking for this law is currently in process, though the provisions took effect starting in 2007. The ICMJE policy requires trial registration of any interventional study, regardless of phase or intervention type; penalty for non-compliance is that a journal will not consider the manuscript for publication. Other key international registration laws and policies are listed at http://clinicaltrials.gov/ct2/manage-recs/background#WhyRegister.

3. Are there certain trials that would be prohibited from being listed on Clinicaltrials.gov? If so, for what reason?

ClinicalTrials.gov accepts information from study sponsors or investigators, anywhere in the world. The only requirements are that a biomedical or health-related study (1) involves human subjects and (2) complies with prevailing laws and regulations (e.g., ethics review).

3b. Follow up. Can you please tell us more about the legal, regulatory, and ethics reviews?

We specifically ask for IRB info (menu of options includes: pending, approved, exempt)—and don’t allow studies to go into “recruiting” or “open” status until they have stated that they have IRB approval. We ask for, but don’t systematically enforce, a copy of at least one IRB letter.  We don’t investigate other aspects of regulatory or legal status—it’s just something that the responsible party has to “certify” to us.  We list the oversight authority as a service so that if there is an alleged problem the public (or we) know what entity might have oversight. This is especially true for non-US studies, for which we might not know anything about the regulatory system.

4. What investigators submit a trial for potential inclusion in Clinicaltrials.gov, how does the Clinicaltrials.gov team determine whether to allow the trial on the website? What kind of vetting is done? Is there an honor system component?

ClinicalTrials.gov contains clinical study information submitted by nearly 12,500 study sponsors including the U.S. Federal government, pharmaceutical and device companies, academic, and international organizations.

ClinicalTrials.gov establishes one Web-based PRS account for each organization (such as a company, university, or medical center) after an application is submitted and reviewed by a staff member. All investigators from that organization who are conducting studies are typically designated as users in this single PRS account. The organization generally designates one or more PRS administrators to manage the account and create logins for additional users.

Each submission goes through a two-step process: (1) automated validation rules to detect missing information for required data elements and clearly invalid data (e.g., characters when numeric data are required) and (2) a manual review process focuses on apparent validity, meaningful entries, logic and internal consistency, and formatting. We do not assess the external validity of submitted information because we do not have a validated “reference standard” against which to check.

5. Does Clinicaltrials.gov have a specific policy about for-profit trials? If there is no formal policy, can you speak to your perspectives on this issue?

No, ClinicalTrials.gov does not have any formal policies regarding for-profit trials. We encourage (universal) registration and results reporting for all clinical studies that comply with prevailing laws and regulations, regardless of funding source and other characteristics. As mentioned previously, we strongly believe that transparency is important for all biomedical or health-related research studies involving humans for both ethical and scientific reasons. (See Why Should I Register and Submit Results? at http://clinicaltrials.gov/ct2/manage-recs/background.)

Our perspective is that, as with any scientific endeavor, clinical research exists in the context of a larger “ecosystem” involving many key stakeholders, including researchers, participants, funders, investigators, regulators, and systematic reviewers. As such, the potential scientific and ethical contributions of a particular study (and design) should be considered within the context of the overall environment. For example, what is already known about the question being studied? What related studies have been conducted and what were their findings? What relevant studies are currently underway?

We see ClinicalTrias.gov as a tool to help people answer such questions before a study is initiated. Once a study is planned, we believe that it needs to be registered and, after complete, summary results need to be reported in order to inform the clinical research enterprise and advance evidence-based medicine.

6. As we discussed, I am concerned about certain trials that are listed on Clinicaltrials.gov because in my view they may be more about generating profit and less about helping patients or generating data. In a general sense is it possible that Clinicaltrials.gov might in the future conduct more vetting of submitted trials? If stakeholders are concerned about certain trials is there a mechanism whereby they can express their concerns to the Clinicaltrials.gov team?

ClinicalTrials.gov is not able to assess the quality of clinical research studies – that is the role of funders, regulators, and ethics review boards, among others. The role of ClinicalTrials.gov is to make information about clinical studies publicly available, allowing others to analyze these data. This includes the ability for stakeholders knowledgeable about particular domains to assess the quality of trials for which information is posted on ClinicalTrials.gov. [Analogy: PubMed provides the public with access to bibliographic information about biomedical articles published in peer-reviewed biomedical journals. Publishers, journal editors, and peer reviewers are responsible for vetting the manuscript before publication. Other researchers can critique published articles, further advancing science.]

In general, we ask stakeholders who detect actual errors in a record posted on ClinicalTrials.gov to contact the organization or person who submitted the information (e.g., Sponsor). For legal concerns, stakeholders should contact the regulatory agency or oversight body that has jurisdiction over that trial.

7. Clinicaltrials.gov does not currently list on the website all the information that it obtains about trials such as the specific IRB conducting oversight. Might there be a mechanism in the future whereby concerned stakeholders could make suggestions about policies related to the website such as including more info like IRB providers, costs that patients have to pay to participate, and such?

HHS will soon be issuing a Notice of Proposed Rulemaking (NPRM) regarding the FDAAA requirements for ClinicalTrials.gov reporting. Once published, the public will have 90 days in which to comment. Many of these issues will be covered (e.g., what information must be submitted, and what information will be made public.)

To be notified about the publication of the NPRM, please subscribe to our FDAAA-UPDATE-L listserv at https://list.nih.gov/cgi-bin/wa.exe?SUBED1=fdaaa-update-l&A=1.

8. What is your vision for the future for Clinicaltrials.gov?

We envision continuing our ongoing, iterative process of making incremental improvements to the ClinicalTrials.gov site. For instance, maintenance of our structured data elements is needed to ensure that new study designs can be represented accurately and searched as the scientific fields evolve. Another important area is keeping abreast of new issues that are of interest to our users so that our records and search engine can be modified, as needed, to support their needs (e.g., patient registries, CER). Ongoing examination of how we categorize stem cell studies, and whether or not we should be requiring the submission of information about whether or not payment is involved, are other examples.

ClinicalTrials.gov provides key stakeholders with a tool that they can use to ensure trial transparency and to monitor and evaluate issues of trial methodology. The ultimate value of this tool will depend on how people use it. This is influenced to a large degree by laws, policies, and the overall incentive structures that influence clinical research. Some of the biggest changes, therefore, are likely to come in the form of new and modified policies that will influence how people use the ClincialTrials.gov system.