So Many Foreign Clinical Trials, So Little Oversight
13 CommentsBy Ed Silverman // June 22nd, 2010 // 11:00 am
The growing number of clinical trials conducted overseas, which drugmakers are pursuing to hold down costs, has increasingly raised concerns about proper regulatory oversight and the welfare of enrolled patients. Over the last couple of years, for instance, GlaxoSmithKline and Wyeth briefly ran into difficulties in other countries (see here and here). And Pfizer recently paid $75 million to settle civil and criminal charges brought by a state government in Nigeria over the 1996 Trovan scandal (back story).
Now, though, a new report quantifies the extent to which drugmakers are researching their meds in other countries and the results suggest the concerns will not go away – 80 percent of drugs approved in 2008 had trials in foreign countries, and 78 percent of all patients were enrolled at foreign sites, according to the US Human & Health Service Inspector General. And 10 drugs approved in 2008 were tested entirely abroad with no patients in the US. Meanwhile, the FDA inspected 1.9 percent of domestic clinical trial sites and just 0.7 percent of foreign sites. And while Western Europe accounted for most foreign trial subjects and sites, Central and South America had the highest average number of subjects per site.
The issue and ensuing worries are not new, of course. An HHS OIG report in September 2001 found that “sponsors have expanded research sites into many countries that appear to have limited experience in clinical trials” and the “FDA cannot assure the same level of human subject protections in foreign trials as domestic ones.” In its latest report, the HHS suggests the FDA should require standardized electronic clinical trial data, create an internal database, inspect trials in more countries and monitor trends in foreign clinical trials not conducted under Investigational New Drug applications. But critics say the findings illustrate the ongoing problems plaguing the FDA.
The report “highlights a very frightening and appalling situation,” Congresswoman Rosa DeLauro, a Connecticut Democrat, tells The New York Times. “By pursuing clinical trials in foreign countries with lower standards and where FDA lacks oversight, the industry is seeking the path of least resistance toward lower costs and higher profits to the detriment of public health.” Adil Shamoo, editor of Accountability in Research, adds that “I think this report just confirms the potential problems with foreign trials. There is less liability, patient recruitment is far easier, the concept of informed consent is not well established, and it’s cheaper.”
Drugmakers and clinical research operators, however, argue that rising costs are a legitimate concern and, moreover, clinical investigators in the US appear less interested in participating in studies. As if the HHS study was anticipated, in fact, a recent survey by the Association of Clinical Research Organizations found that between 2004 and 2007, the number of clinical trial investigators who are regulated by the FDA fell 5.2 percent in the US and 6.1 percent in Western Europe, while increasing 16 percent in Eastern Europe, 12 percent in Asia and 10 percent in Latin America.
The reasons cited by US investigators: regulations make trials difficult to manage, medical liability, and conflict of interest mandates that docs disclose financial relationships with pharma. In fact, 24 percent of US investigators are less likely to participate in trials if they are required to disclose income. And US investigators are more concerned with making money – 68 percent say this is a “very important” factor in their participation (read more here).
UPDATE: At about 4:30 pm EST, the PhRMA trade group writes us to say that the same regulatory standards apply to foreign trials as those conducted in the US. “Is it ethical to conduct such studies outside of the US? In a word: Yes. Whether the clinical research occurs in the US or outside its borders, our member companies must adhere to Good Clinical Practice guidelines.
“In fact, PhRMA has conducted educational seminars and symposiums – at times, in conjunction with the FDA – in other countries to educate potential clinical trial principal investigators about Good Clinical Practices, ethics oversight by outside review boards, and the need to maintain the highest standards for data quality.
“Regardless of the location, however, companies seeking US approval must maintain the FDA’s high standards for conducting the trial. For instance, any related trials conducted outside the U.S. must comply with FDA requirements covering Good Clinical Practices, in addition to meeting the requirements mandated in these important emerging markets.” Here is the complete PhRMA statement.
Don
So Congresswoman DeLauro thinks that in this global economy ex-U.S. clinical trials are sub-standard, and risky? Perhaps she can reconcile this opinion with her position in favor of drug-reimportation from foreign countries, consumed by U.S. citizens, and that will lack serious FDA oversight.
SteveM
Re: Don “drug-reimportation from foreign countries…”
That whole concept is so logistically perverse. The manufacturer/distributor should just attach a sign that says “Canada” to their warehouse in the States and just pretend the stuff goes out and back.
DCInsider
This information and the accompanying stats are not new. This report could have easily been written five years ago – or in five years to come. What I’m more interested in is the analysis of the info/stats. Does it matter that drugs consumed in the US are not tested in the US? Okay let’s assume that US PI involvement drops to nil – is that a good or a bad thing? How is it a “frightening and appalling situation” and “to the detriment of public health”? Is DeLauro concerned about citizens of India, Serbia, etc. or does her comment reflect her concern for citizens of Connecticut?
LF Velez
When I was at the Drug Information Association meeting last week in DC, there were dozens of clinical research organizations, many from overseas, looking to recruit people to run their trials through x or y CRO. Would I like participants from Japan? Belarus? Italy? Russia? Would I like to have my materials reviewed by the fastest IRB, the busiest, or the one that most strongly proclaimed its concern for the welfare of participants?
And would I like to pause a few minutes with my coffee to watch Spain lose its opening World Cup match? [Yes, thank you -- pain is best shared...]
I don’t object to companies competing for business, but one does have to wonder: if so much of future medicine is going to be based on genomic differences, what good will it do to run trials of drugs on people in less expensive regions of the world if the people who really will be buying those drugs are from very different ethnic groups and environmental experiences?
pharmavet
I have no opinion on this matter. However, the stark reality is that in certain countries, particularly in eastern europe and I’m sure elsewhere, participation in clinical drug trials is the only way for many people to get access to health care that would otherwise not be available to them. This is little different from the situation in the US where many patients participate in trials because they lack health insurance. The carrot is that if the drug under study is eventually approved these patients may have access to free drug for an extended period of time. I agree that this is a sub-ideal way to gain access to in some cases life-saving medications, but for many such folks it is their only option.
John Lewis
The Association of Clinical Research Organizations (ACRO) supports the recommendations outlined in the HHS report, and we have been actively advocating for increased funding for the FDA’s Office of International Programs (OIP) to provide the agency with sufficient resources to ensure research quality is maintained around the world. The association continues to encourage development of a robust global research infrastructure to facilitate accelerated drug development.
Our members are committed to the highest levels of patient safety and research quality and are global leaders in adherence to good clinical practice (GCP) principles set by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). CROs train research staff around the world in GCP principles and proof of compliance is required by drug regulators in every major pharmaceutical market. The association believes that all participants in clinical research – no matter where they live or the environment in which research takes place – must be protected by the same level of safety, ethical considerations and standards of care.
We promote efforts to strengthen the globalization of the clinical research enterprise in order to speed the development of life-saving medicines and treatments for patients who need them. Findings from a July 2009 study concluded that globalized trials can reduce development time by more than half while maintaining quality and safety. ACRO will continue its efforts to collaborate with stakeholders around the world to enhance clinical development and encourage clinical research participation.
jamzo
relying on poor people as guinea pigs for drug experiments seems like a primitive and cruel business model
what would pharma do to test drugs if there everyone had inexpensive health care and didn’t have any motivation to participate in drug trials
LF Velez
Then the trials would have to be testing treatments for conditions that currently don’t respond to approved medications, or for people who don’t get sufficient improvement in their conditions from approved medications…
When nothing is working for you, or you are told there is nothing available that could work for you, there’s plenty of motivation to try SOMETHING.
pharmavet
Jamzo, the pharma industry is 10 steps ahead of the game. You are correct; having universal health insurance is demotivating to be in a clinical trial, hence the jump to run trials ex-US. However if it is for a class of drug that Dr Ezekiel Emmanuel of the National United States Government-Mandated Formulary denies (better believe this will happen) then you are back to volunteering for clinical trials.
I may get hammered for this but when we did clinical trials in prison populations they were very well done, better than in the general population IMHO. They were stopped because the ethicists who never stepped inside a prison wall decided that such trials were inherently coercive if subjects feared repercussions from withdrawing from trials, although this was more of a theoretical than practical concern. I would not have a problem going back to prisoners to get the studies back in the US.
cliffintokyo
PV:
Go directly to Jail. Do not pass *GO*. Do not collect *FDA* bonus. Do a PhRMA *double-take* to get out.
pharmavet
Cliff, sometimes studies in captive populations yield the best results because of their controlled nature. For example, much of what we learned about the metabolism of harmful cholesterol was learned from boarding school studies in which radioactive cholesterol was admixed with students’ breakfast food. The boys’ health was followed for a number of years afterward, and while no ill effects were observed, their contribution to medical science was large indeed.
pharmasherpa
Who can object to wanting to ensure that patients are properly protected when conducting international trials?
I object to Congresswoman DeLauro’s statements (by pursuing clinical trials in foreign countries with lower standards where FDA lacks oversight, industry is seeking lower costs to the detriment of public health).
If submitting in the US, FDA regulations (including GCP) will apply regardless of where the study is conducted.
It is the public health in the US that is the beneficiary of lower-cost trials abroad, as they enable medicines to be tested, approved, and commercialized that may not otherwise have done so due to cost limitations.
DeLauro’s comments are rather paternalistic, implying that the world requires FDA oversight for protection. Especially when she concurrently supports drugs to be reimported to the US (showing a convenient anti-pharma mix of confidence in ex-US regulatory oversight).
cliffintokyo
PV:
So, you spotted that my comment was intended to be *tongue-in-cheek*!
As you say, there is probably no real harm in performing properly conducted CT in prison populations. The ethnic cross-section available may actually help to satisfy the *intrinsic* requirements of ICH E5. Not sure that the extrinsic requirements of E5 would stand up to comparison with the population at large though (prison food, drug use, exercise, air quality……?)