Stem cell clinics, FDA, and giant, unapproved for-profit human experiments

When I started blogging in 2010 the stem cell arena was a very different place.

Back then the hot topic was the battle over the legality of federal funding of embryonic stem cell research. That battle is over, or at least in hibernation, with a 2013 federal court ruling allowing such funding to continue. The stem cell debate of today, which in its own way is just as fierce as the old one, is focused on how best to regulate the clinical translation and commercialization of innovative stem cell technologies.

The stakes in this new stem cell battle on the regulatory front are very high both for the stem cell field and for patients. Too little regulation could lead to harm to patients and damage to the stem cell field at a crucial juncture in its history, while too much regulation could stifle stem cell and regenerative medicine innovations.

Stem cell clinics should be better-regulated than a Starbucks

The goal of stem cell advocates, including myself, is to find a regulatory sweet spot where science-based, innovative stem cell medicine can advance expeditiously. On the other side we have largely physicians and lawyers along with some patients arguing for drastically-reduced regulation and acceleration of for-profit stem cell interventions to patients, even without concrete data supporting safety or efficacy.

The latter group is a key part of a rapidly-proliferating stem cell clinic industry in the US. It consists of for-profit stem cell clinics that collectively have already conducted stem cell transplants on potentially thousands of patients without federal regulatory approval. These clinics have in effect thrown down the gauntlet to the US Food and Drug Administration (FDA) with their use of non-FDA approved stem cell products on patients. 

Role and authority of the FDA

The FDA is the regulatory body legally empowered to regulate biologic products and hence stem cells in the US. However, the clinics generally argue that they and their stem cell products should not be regulated by the FDA because they believe that the products are not drugs and they as the physicians transplanting the stem cells are just conducting “the practice of medicine”. FDA guidance over the years has consistently conflicted with this view and indicated to the contrary that these clinics are generally producing a stem cell product that is a biological drug. Even so the clinics at this time do not have FDA approval to make and use stem cell biological drugs. Such approval can come in response to what is called an Investigational New Drug (IND) application. The clinics do not have IND approval from the FDA for their stem cell products or devices and do not have the licensing (called a Biological License Application or BLA) needed to produce and administer biological drug products such as certain types of stem cells. Collectively, for these reasons (absence of BLA and INDs), I define such clinics as “unlicensed” and their products as “unapproved” or “unproven”. Note that the physicians practicing at such clinics generally do have medical licenses from state medical boards, so they personally are licensed in that sense. These clinic physicians frequently further point out that doctors themselves can only be directly regulated by state medical boards and not by the FDA.

Where does the FDA get its authority to regulate stem cell products and clinics? The Federal Food, Drug, and Cosmetic (FDC) Act and the Public Health Service (PHS) Act give the FDA the legal authority and responsibility to regulate biologics including human stem cells. Therefore, barring a federal court specifically overturning a particular FDA decision, FDA regulations are essentially law when it comes to clinical use of stem cells in the US. The FDA is given certain authority over stem cell biological products and procedures more specifically under several regulations including “21 CFR Part 1271.10“, modified by “21 CFR 1271.15“, which details exceptions to its regulatory requirements. A key term to know before trying to decipher the verbiage in these regulations is “human cell and tissue products” or “HCT/Ps”, which basically means human biological products including human stem cells.

The state of the market

Both individual doctors doing stem cell transplants and chains of dozens of stem cell clinics have sprouted up from coast to coast in the US in the last few years. These clinics, collectively numbering more than 20 in the state of Texas alone and more than 100 across America, are administering stem cell transplants of one kind or another to growing numbers of patients each year, potentially generating millions of dollars in income, all without FDA approval. In doing so many of these clinics, even absent litigation against the FDA, are operationally challenging and undermining the authority of the agency by acting as medical providers using stem cell products without FDA approval or licensing. They are also a direct challenge to science-based medicine more generally. To put it more bluntly, I believe these clinics are in essence collectively doing a huge, unapproved human experiment for profit.

The FDA has issued a steady stream of regulatory guidances, supported in some cases by court decisions (e.g. US v. Regenerative Sciences Inc.), painting a clear picture that stem cell clinics in a general sense (as well as their products, devices, and procedures) are within its regulatory domain and their products can be defined as biological drugs. Furthermore, in 2012 and 2013 the FDA took numerous actions related to stem cell clinics such as warning letters issued to a number of clinics including the Texas stem cell clinic Celltex, which is well-known for having treated Governor Rick Perry.

Strangely the FDA took no regulatory action regarding stem cell clinics in 2014, at least none that is evident in the public domain, but the FDA did issue important new draft guidances related to stem cells (see herehere, and here) that I predict will be the basis for future action. One part of these guidances focuses on “minimal manipulation“, which is a key term in the stem cell clinical world and more broadly the world of biologics. If a biological product is defined as more than minimally manipulated it automatically leads that product to be defined as a biological drug subject to the full spectrum of drug regulatory oversight by the FDA. While stem cell clinics frequently argue that their products are less than minimally manipulated, it is becoming clearer that a large fraction of (but certainly not all) stem cell products sold by various clinics are likely to be viewed by the FDA as more than minimally manipulated.

The FDA and the stem cell therapy industry use numeric names for products that are minimally manipulated (361) or more than minimally manipulated (351), so these can be important to know as one navigates this arena. The for-profit stem cell clinics generally argue that their products are 361s, but I believe that FDA guidance indicates instead that a large number of these products are 351 biological drugs.

Treatment types, guidance and loopholes

It is also valuable at this point to talk about the different kinds of stem cell “treatments” sold by dubious clinics. The most common stem cell product transplanted into patients is something called stromal vascular fraction or SVF, which is a product manufactured from fat tissue. While various clinics use other stem cell products including cells isolated from bone marrow and other tissues (some of which may be 361s, while others are 351s), SVF is by far the most common stem cell product sold by clinics.

 Stromal vascular fraction, an extract of cleaned, centrifuged stem cells derived from body fat.

Amongst other things, the new draft FDA guidances explicitly single out SVF for attention and define it as a biological drug. This is particularly notable because many stem cell clinics have argued that SVF is not a drug and hence is not subject to drug-related FDA vetting. While many including myself have asserted in the past that SVF is almost certainly a drug and needs FDA approval before use, these new guidances from the FDA articulate, far more specifically and unambiguously than in the past, how SVF is by definition more than minimally manipulated and hence a drug (emphasis mine):

Example A-1: Adipose tissue is recovered by tumescent liposuction. The adipose tissue undergoes processing or manipulation (e.g., enzymatic digestion, mechanical disruption, etc.) to isolate cellular components, commonly referred to as stromal vascular fraction, which is considered a potential source of adipose-derived stromal/stem cells for clinical therapeutic uses. This processing breaks down and eliminates the structural components that function to provide cushioning and support, thereby altering the original relevant characteristics of the HCT/P relating to its utility for reconstruction, repair, or replacement. Therefore, based on the definition of minimal manipulation for structural tissue, this processing would generally be considered more than minimal manipulation.

Because of these new FDA guidances, I believe the fat stem cell clinic industry could be subject to future FDA action. However, the FDA is slow and cautious in how it proceeds with even what seem to be relatively straightforward regulatory actions that could even be viewed as neutral such as simply visiting a stem cell clinic to obtain information on its practices, products, devices, and such. It is important that the science-based medicine community advocate for appropriate, expeditious FDA action.

Another key term in the stem cell clinical arena is “homologous use“. When applied to an HCT/P product, it means that the clinical use of that product must be highly consistent with (i.e. homologous to) the properties of the original tissue from which the product was made; if it is not homologous, even if minimally manipulated it will automatically be considered a 351 drug product. An example of homologous use would be the transplant of hematopoietic stem cells to treat a hematopoietic disorder. In that case, a blood-related product is used to treat a blood-related disease.

An example of non-homologous use would be the transplant of SVF (again, a fat tissue derivative) as an intervention for a neurological disorder, as fat is not homologous to the nervous system. In this regard, it is important to point out that many stem cell clinics offer up their stem cell products (most often SVF) to “treat” a whole menu of human diseases manifesting in tissues that having nothing to do with fat or with the other tissues of origin of the various types of stem cells.

In an example given in the new draft FDA guidance in the section on homologous use, the agency points out that use of SVF to treat a bone or joint disease is non-homologous use (emphasis mine):

Example B-2: Adipose tissue is recovered and processed for use, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent, to treat bone and joint disease. Because adipose tissue does not perform this function in the donor, using HCT/Ps from adipose tissue to treat bone and joint disease is generally considered a non-homologous use.

Another way that clinics try to get around having their products defined as biological drugs is through a possible FDA exception called “same surgical procedure“. The idea here is that if a procedure involving biologics such as stem cells is done in an autologous manner (the patient is both donor and recipient) and is completed in a single surgical procedure, then the biological product in theory might not be defined as a biological drug. It might be exempt from that designation because such procedures may have relatively lower risks. Many stem cell clinics have made the assertion that because in some cases they use stem cells in same surgical procedures that it means that they are not subject to FDA regulation of their product as a drug even if the product is, for example, SVF. However, the reality appears to be that the “more than minimal manipulation” and “non-homologous use” definitions trump the same surgical procedure exemption, discussed further in one of the 2014 draft FDA guidances mentioned earlier. What this means is that if your product is more than minimally manipulated or it is used in a non-homologous manner (either of these is enough), it is still automatically defined as a biological drug even if you use it in a same-day surgical procedure.

Stem cell clinic chains

The point of these FDA biologics regulations is to protect patients. It is logical that products that are more than minimally manipulated or used in a non-homologous manner pose higher risks to patients. As a result there is an appropriately higher requirement for evidence to support the use of such products in human patients. It is therefore of substantial concern that so many stem cell clinics in the US and around the world are going ahead and using experimental stem cell drugs as the basis of for-profit interventions without evidence that such products are safe or effective.

The stem cell entities in the US that concern me the most are chains of stem cell franchising clinics. These are rapidly-growing chains of affiliated clinics selling mostly fat stem cell-based interventions without FDA approval or licensing. Two examples of such chains are Cell Surgical Network and Stem.md.

Cell Surgical Network

Cell Surgical Network is a Beverly Hills-based chain of upwards of 50 stem cell clinics around the US that share philosophies, institutional review boards (IRB), procedures, devices, and malpractice insurance. They offer up SVF-based interventions for a wide range of medical conditions. I interviewed the leaders of Cell Surgical Network, Drs. Elliot Lander and Mark Berman, on my own blog last year (see here and here) and then raised my concerns about their operations, including my view that their SVF product is likely more than minimally manipulated, that they use the product in what I view as a non-homologous manner, and that the device they use is not FDA-approved for this application. Their device is a column, which is a laboratory tool used to separate cells from the rest of the components of tissues, manufactured by a company called “Medikan”.

In response to my question regarding the possibility that the Cell Surgical Network SVF product is a 351 biological drug (and one for which they do not have FDA approval such as an IND to use it clinically), Cell Surgical Network responded in part by invoking the same-day surgical exemption, which again to my knowledge does not apply in this case with SVF:

We produce SVF (over 40 ingredients and can’t be characterized) in a surgical procedure (can’t be approved by the FDA – they’ve never approved a surgical procedure). If the FDA can’t approve a surgical procedure, why would we possibly request them to approve this procedure?

It is worth noting that although arguably the FDA cannot directly regulate doctors or surgical procedures, the FDA can and does regulate drug products, biologics production procedures and devices in a general sense, which largely challenges the Cell Surgical Network’s argument as well.

I also asked Cell Surgical Network about the issue of their arguably non-homologous use of SVF to treat diverse non-fat related conditions (see their menu here). I found their response to be rather creative, but one with which I disagree:

We do have many conditions that we are looking at and in choosing them we have attempted to exploit either the regenerative, immuno-modulatory, or anti-inflammatory properties of SVF. Although SVF is used in all of our protocols, our deployment techniques vary considerably. I think the term homologous has been used rather loosely and in the field of regenerative medicine, a new paradigm defies simplistic categorizations of cell types. After all, what type of tissue is an undifferentiated progenitor cell? Can it be homologous? Isn’t it potentially everything? For example, if it forms cartilage then could it have ever been anything other than a cartilage precursor? Our comfort zone is that we are surgeons performing a type of surgical tissue transfer procedure. There is no difference than when we replace a bladder with ileum or a coronary artery with a saphenous vein from an extremity. At the end of the day, the ability to use various tissues to treat human disease is within the realm of a surgeon’s domain.

In this line of argument then, would anything stem cell-related be considered “pan-homologous” to every other tissue and could never be used in a non-homologous manner? That seems like a rather radical notion and one not consistent with FDA guidance. Further, can a surgeon pretty much do anything they want? That seems to be a rather extreme idea too.

Still, despite these concerns, to my knowledge the FDA has so far never taken any action related to Cell Surgical Network. Therefore, a reasonable question to ask is why, if from my perspective the FDA would view Cell Surgical Network as likely being non-compliant in its use of stem cells, has the agency apparently done nothing about it? The frank answer is that no one except the FDA knows why or why not they take specific actions and they do publicly discuss specific situations.

Stem.md

Stem.md is a similar group of stem cell clinics, but one that sprouted up on the East Coast. Stem.md has dozens of clinics too, including some using SVF as well as other types of stem cell products. While the Stem.md website frequently has changed over the years, as recently as a year ago they made some rather bold claims for their stem cell transplants including the remarkable statement that they “provide a treatment for every condition”. Sounds like a panacea, right? They also at one point claimed their “advances” were FDA-approved, although they took down that claim when I pointed it out to them as being incorrect. Like some other stem cell clinics, Stem.md has made a big deal out of treating pro athletes, including in their case former Yankee Bartolo Colon, which might remind you of the recent case where stem cell clinics Stemedica and Novastem arguably could have benefited from a free stem cell intervention performed on hockey legend Gordie Howe as a public relations opportunity.

Some of the same nagging issues come up with Stem.md as with Cell Surgical Network, including potential non-homologous use and more-than-minimal manipulation. However, as with Cell Surgical Network, to my knowledge the FDA has not taken any regulatory action related to Stem.md.

While the recent FDA draft guidances are a step in the right direction of increased clarity, if the FDA takes no action, or waits years to enforce its finalized guidances, the end result is that the FDA is undermining its own authority and I believe putting patients at increased risk. In principle, in the absence of FDA action, stem cell clinics can effectively argue that if their practices did violate FDA regulations then the FDA should have done something about it by now. In the absence of regulatory action, there is always the possibility that the FDA could view the clinics’ use of stem cell products as compliant. I would also note that my views presented in this article, of course, do not necessarily reflect those of the FDA, and the stem cell clinics view FDA regulations quite differently.

The role of ClinicalTrials.gov

A relatively newer, but important issue related to stem cell clinics is the listing of their stem cell interventions on the official US government’s clinical trials website, ClinicalTrials.gov. I recently interviewed the Director of ClinicalTrials.gov, Dr. Deborah Zarin, to ask her about key issues including specific questions related to stem cell clinic listings. I was concerned to find out that ClinicalTrials.gov largely operates on the honor system in terms of deciding whether to list trials submitted to it for consideration. For example, there is neither specific vetting of US trials (keep in mind that ClinicalTrials.gov lists trials from all over the world) for FDA compliance nor a requirement that trials list specific IRB or other key information. Trials listed on the database can also be of a for-profit nature (i.e. patients are charged simply for participating in the trial before there is concrete evidence that the product or procedure in question is safe or effective) and based on the information in the trial listing, there is no straightforward way for patients to know that reality. I believe that this situation puts patients at added risk and also puts the valuable mission of ClinicalTrials.gov in jeopardy.

The end result of this situation is that many for-profit stem cell clinics have trials listed on ClinicalTrials.gov and some use that listing as a marketing tool. What kind of money is involved here? Cell Surgical Network has a clinical trial listed with a projected enrollment of 3,000 patients and hypothetically if the organization makes $5,000 profit per patient that would add up to $15 million, again before the SVF product in question is even known to be safe or effective for the particular condition in question and without FDA approval or licensing.

I believe that a number of changes are needed at ClinicalTrials.gov including a requirement that for-profit trials be labeled clearly as such near the top of their listing page, that the listing of a given trial on the site should be prohibited from being used as a marketing tool by the entity responsible for the trial, and that the ClinicalTrial.gov team vet trials located in the US for FDA compliance and as needed consult with the FDA on this matter.

If you feel likewise, this is one case where you can easily take positive action during a specific window of time. ClinicalTrials.gov has issued a Notice of Proposed Rule Making (NPRM), detailed in a very recent open access New England Journal of Medicine article by Dr. Zarin. Comments on proposed changes including suggestions such as mine can be submitted in response to this NRPM, but only until February 19th. I encourage you to submit comments and I have dug through the websites to find this direct link that allows you to do so quickly and easily.

Conclusion

The overall bottom line with most stem cell clinics in the US is that collectively they could be viewed as conducting a huge, unapproved and for-profit stem cell experiment of a sort, on thousands of vulnerable patients who are often desperately looking for hope. At the very least these patients are spending money that they can ill afford to lose on stem cell transplants that probably do not help them. It is also quite possible that some of these patients are being harmed. Stem cells do not always do what we might hope and their power to potentially help patients is equaled by their potential to do harm, especially when not backed up by rigorous science and physician training. For example, fat stem cells are typically a heterogeneous mix of a variety of cell types with variable multipotency – meaning that they can not only form mature fat tissue, but also potentially blood vessels, bone, cartilage, or others. The growth of an undesired tissue in the wrong place could be a major adverse outcome. There is evidence of potential for patient harm including growth of bone in an eye and nose tissue in a spine from stem cell treatments that went awry. Some patients treated at stem cell clinics have died, including in the USGermany, and elsewhere.

More broadly in this new stem cell debate, the for-profit clinic argument for stem cell deregulation and weakening of the FDA’s role in regulating stem cell products is a direct challenge to our system of science-based medicine. Furthermore, while to those of us in the stem cell field it may often seem clear where we can place a dividing line between the dubious clinics and the ones who follow the rules, that line is at best fuzzy for the wider community (including patients). For this reason the ever-growing unapproved human stem cell experiment poses a grave risk to the legitimate stem cell field as well. Governmental entities such as the FDA and ClinicalTrials.gov perform important services in this arena, but can and should do better to reign in the “wild west” mentality of the stem cell clinic industry in America today. Advocates of science-based medicine have an opportunity to make a positive impact here as well via educational outreach, participation in the FDA guidance comment process, and advocacy for responsible clinical research.

Note: a version of this piece was first posted at Sciencebasedmedicine.org.

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.