FDA Scraps Helsinki Rule On Human Subjects
22 CommentsBy Ed Silverman // May 9th, 2008 // 1:10 pm
Drugmakers will soon be able to use data from foreign clinical trials in new drug applications even if trials only compare new products to placebos instead of best available treatments. The change departs from the 1989 Declaration of Helsinki protecting human subjects in clinical research, the FDA’s previous standard, according to Integrity in Science Watch.
The new rule’s substitute standard says foreign trials should follow good clinical practices and include a review and approval by an independent ethics committee. A major difference between the Helsinki Declaration and GCP is the former’s insistence on using existing treatments instead of placebos if they are available, ISW writes, adding that the Helsinki Declaration had the effect of extending existing treatments to people in poor countries if they participated in clinical trials.
The change, which goes into effect in Octoer, is likely to push more clinical trials abroad, where an estimated 35 percent of all trials submitted to the FDA in new drug applications now take place, according to ISW. Unlike trials conducted in the US, drugmakers don’t have to submit an investigational new drug application (IND) to the FDA before beginning research in foreign countries.
The FDA estimates about 575 of the foreign trials submitted agency each year as part of an NDA don’t go through the IND process. The FDA rejected the notion that adopting the self-regulating GCP standard and eliminating references to the Helsinki Declaration “will hurt subjects in developing countries or result in less protection for subjects in foreign studies.” GCP requires trial sponsors closely monitor trial behavior and report adverse events, the agency noted.
Jack2
I don’t really understand this. I’ve seen tons of trials in the past few years comparing to placebo.
M Helm, MD
This is a fairly horrifying development, and a clear step in the wrong direction, in my opinion. The question with new drugs is almost never “is this better than nothing?” Increasingly, clinicians, consumers, and payers need to know whether or not a new treatment is better than other existing comparable treatments. (This means comparing one product to another equally potent/equally effective treatment option - not for example like the study which compared esomeprazole 40mg to omeprazole 20mg.)
I hope:
1) US, Japanese and EU research-based manufacturers (at a minimum) do not allow themselves to go this route,
2) the next administration will revisit the standards of acceptable science to ensure that pharmaceutical and devices continue to represent innovation and improvement, and
3) The presciber and consumer communities demand a higher level of scientific scrutiny (and ethics in study design)prior to latching onto new medications which may have only been studied versus placebo (where other clearly effective treatments are available).
Recently we saw the approval of aripiprazole for schizophrenia in adolescents. As I recall from what I could find of the research, most of the young patients studied were from eastern europe. The control group in the trial received a placebo, despite that they were experiencing psychosis, and despite that there are a number of older antipsychotics whose use is approved in children even younger than the study population. I would never dream of subjecting my child (or a child I cared for) to this kind of experiment when I know other effective medications are available.
I admit that finding information on the aripiprazole trials done for FDA approval in adolescents was difficult for me. The results had not been published the last time I looked for them, so my information comes from news releases and press stories. If I have any of this story wrong, I welcome correction - I’d like to think this is not really the way this all happened.
I remember early work on leviteracetam (an antiepileptic) gave hope that through it’s unique action it might be a useful primary treatment. However, at the time it was not considered ethical to withhold treatment with one of the three primary siezure medications. Consequently, leviteracetam came to market as an “adjunct” treatment. this may have somewhat slowed adoption, but it certainly gave clincians confidence that the product did something more than what they were already using.
HorusCat
Matt,
I, like Jack2, am a little confused. We see placebo-controlled trials here in the US all the time. In fact, in some instances the FDA mandates placebo controls. This was the case with the antipsychotics last I checked. When I worked for Big Blue and ziprasidone came out, the pivotal trials were placebo-controlled and most were done here in the States or Western Europe. MS studies are still done vs placebo, which makes it hard to recruit for them. I suspect the rules vary according to disease state.
I would guess that the aripiprazole adolescent trials were done in Eastern Europe because it is far easier to recruit for trials there, especially for kids. It is notoriously difficult to fill child trials here in the States, for obvious reasons.
I agree with you, though, in finding this horrifying. There are just too many opportunities for this to go REALLY bad.
Joana Ramos
Here is some helpful background on this topic, which explains significance of the FDA decision. This is just one of much that has been written on this subject about which which we hear far too little about here in the USA. Full text article is available at link.
http://www.nature.com/embor/journal/v7/n7/full/7400743.html
EMBO reports 7, 7, 670–672 (2006)
The battle of Helsinki: Two troublesome paragraphs in the Declaration of Helsinki are causing a furore over medical research ethics.
> Howard Wolinsky
> Later this year, the US Food and Drug Administration (FDA; Rockville, MD, USA) plans to rewrite its regulations to eliminate any reference to the Declaration of Helsinki (DoH), a document from the World Medical Association (WMA; Ferney-le-Voltaire, France) that many consider to be the hallmark of medical ethics (WMA, 2004). This decision, triggered by the 2000 update to the DoH, is the latest move in an increasingly heated debate over medical research ethics. The FDA is reacting in particular to the addition of two controversial paragraphs, which, if adopted in their own regulations, would limit the use of placebos in drug trials and increase the responsibilities of trial sponsors towards research participants. …
Former pharma Marketing Exec
I agree with all here, this is a truly despicable situation and shame on the FDA.
Does the American public need any further proof of how the FDA has been bought off by Pharma money - if so then this is clearly it.
I think we need to start talking in terms of rotating drug company boycotts much like the ones being suggested and implemented against the various gas/oil companies.
It’s petition time….
Justice in Michigan
Couple of points.
As I understand it, FDA’s _general_ standard of efficacy is, indeed, that drug X is better than nothing (placebo) at .05 level of significance.
But it sounds like the trials at issue include people who ought to be on some sort of tx. So that providing them with nothing - rather than an existing tx - is a different situation.
Beyond this particular issue, the pattern of rule-making by the Bush FDA is clear:
- The preemption preamble of 2007
- The attempt to limit manufacturer’s obligations to report emerging risks - revising the CBE language.
- The attempt to open the door fully to off-label promotion.
- And this latest that will open the door to deregulate the protection of human subjects
Many here will know that it was only after thalidomide, via Kefauver-Harris in the 1960s, that there was any human subject protection at all regulated by FDA. There was also an attempt in the 1990s to get rid of it when Gingrich, et. al. were attempting to dissolve FDA entirely. The rest of the agenda is also pretty much the same as what was attempted in the ’90s (and had its successes - DTC on an unpredented scale; much grayer regulation of promoting unapproved applications.)
All of this (and probably more to come) may, in retrospect, be looked back upon as the death throes of a radical deregulatory movement.
It may also be the beginning of a regulatory dark ages.
Bob Freeman
Justice, I agree with all of your points. The impact of safety may be more of an untoward event than a regulatory intent.
The only perspective I would add is that randomized, placebo-controlled trials are the norm, two in fact, for regulatory approval. When it is unethical to withhold standard therapy from patients with certain diseases (cancer, AIDS, etc.) comparator RCTs are conducted. A lot of the comparator trials that are conducted test the hypotheis of equal efficacy of the new drug with the comparator or, in some instances, non-inferiority. One of the trends has been to show equal efficacy but a better safety profile.
Justice in Michigan
Thanks, Bob. I was assuming some version of what you explained but was not certain that of where the line was. The article in Nature that Joana cites has Bob Temple worrying that Helsinki was somehow going to infringe on the normal process of RCTs with placebos.
Here, I am guessing (but only that) that this is connected with the usual push against anything that could open the door to head-to-head efficacy trials more generally.
Bob Freeman
Good morning, Justice. I just reread what I wrote and don’t see where the nexus with your post is either. I may have been unconsciously linking back to another’s post.
Justice in Michigan
Uh oh….I hope you’re not “channeling” posts. But I did see a connection, so I guess the channel is in the mind of the whomever!
Just in case there’s a question (this for others), I do not see the “regulatory dark ages” I describe as any kind of victory for the industry. It would be a disaster for everyone.
Thus, it was especially the industry - Eve Slater at Merck was particularly outspoken - that put the breaks on Gingrich. And it was the bipartisan Subcommittee on Health in the House (which had a conservatative Republican majority) which also did.
Good companies with good management don’t need to be told what science and responsibility mean. Thus, many were already doing the kinds of trials that Kefauver-Harris required before the bill became law. As noted on other threads, a number turned down thalidomide because they knew there was no reliable science behind it, and what there was was suspect at best.
Former Pharmaceutical Marketing Executive
Unfortunately I have seen that they have used placebo’s in a cancer trial. A good friend of mine is now dead because he agreed to be in the trial. I could not convince him to opt out of the trial because he couldn’t see that anyone would do something so ethical as set up a trial that did not offer the chance at the current standard of therapy versus a new drug in a clinical trial. So, being on the “placebo” for a few months meant that his cancer seriously progressed to the point that treatment would no longer benefit him. His family is still in a state of shock.
Just recently a big pharma company completed a placebo/versus drug trial for kidney cancer. There is current treatment for kidney cancer. How many kidney cancer patients died in the cours eof this trial?
Much like Justice, we need to look at the overall impact to humanity. Even within a well regulated system we see many instances of rule breaking. How does the FDA think the industry could ethically self regulate on this one.
Is it me, or is anyone else seeing the inconsistnecy in the way the FDA is approaching such critical issues.
I have a contract this year that means I will be attending ASCO. I will be on the look out for the cancer patients and what they are saying to the FDA on these issues.
By the way, I wouldn’t have suggested boycotts and petitions without the benefit of experience in knowing that they are effective and work nicely. Historically, the most dramatic change comes when the workers and the working class rise up and say enough! If Pharma and the FDA are bent on treating patients as consumers then the patients must exercise their consumer rights.
Jack2
FPME, got citations for these trials?
Nathan
FPME says: “unfortunately I have seen that they have used placebo’s in a cancer trial. A good friend of mine is now dead because he agreed to be in the trial.”
How do you know that your friend was on the placebo end of the trial? I thought that patients generally never found out which arm of the trial that they were in. Could it simply be that the drug failed? As I’m sure you know, the efficacy of cancer drugs is notoriously unpredictable. We’ve created miracle drugs for rats that fail to do a thing in humans.
James
Hate to tell you guys, but the reason the FDA went with this standard instead of the one initially proposed in the draft guidance 4 years ago is…
this is how they’ve been doing things already. Nothing new.
Former pharma Marketing Exec
Jack2 - Yes I have citations, but no I am not sharing them here - sorry hate to be secretive but there is already a law suit in the works and well, I would rather not be the one who spoils it…
Nathan, the patient knew he was in the placebo because he was actually getting nothing…..No radiation, no chemo - nothing…Bizarre as it all sounds.
Heart Breaking…
M Helm, MD
FPME,
I’m very sorry about your friend. I would be willing to bet that the trial was administered by a Contract Research Organization. I can not imagine a research institute/ university Institutional Review Board would approve such a trial.
But, CROs are a different ethical problem.
Bob Freeman
The only “placeo” I can think of in a cancer trial is watchful waiting in men over a certain age who have prostate CA. (I’m not fishing for information, FPME, just thinking out loud. I am sorry for the loss of your friend)
I recall one breast cancer trial that compared agressive lab work as the control vs. tamoxifen for bc risk reduction. That was not an industry trial–It was the Eastern Oncology Group, I believe.
To Matt, if I never work with a CRO again it will be too soon.
RTW
The FDA has been pushing to do placebo controlled trials in oncology to presumably get a better picture of the efficacy of anticancer drugs. Almost all oncologists would be very squeamish about this, and it would be tantamount to dividing a group of cancer patients into two camps randomly, one of which isn’t getting any treatment. Cancer trials have always compared standard treatment to new and usually combination therapy. Additionally Cancer trials are as much about the new drug as the protocol for administering it.
Placebo controlled trials are not as big an ethical consideration in CNS, and cardiovascular indications where the threat to ones immediate well being isn’t as great as it might be in Viral, Bacterial and Cancer indications. Millions walk around untreated for high BP, depression, pain etc, but their conditions are not likely to progress that much more into an irreversible state from which even the best treatment won’t bring you back as it does when dealing with Viral, Bacterial infections and cancer.
Bob Freeman
Thanks, RTW. Could you clarify a point? when a new oncology drug is developed for refractory patients what is the standard of care? anyone of a number of cocktails vs. the cocktail plus the new drug? Thanks in advance.
It’s been a while since I’ve looked at oncology trials and would appreciate an update.
I completely agree with the reluctance to use a placeo-controlled trial for a cancer patient, regardless of Stage.
Nathan
FPME — that is heartbreaking — but I don’t think you can infer anything about big pharma clinical trials based on that experience. That was not a placebo controled trial. The definition of a placebo is: “a substance having no pharmacological effect but given merely to satisfy a patient who supposes it to be a medicine.”
Your friend seems to have gotten into some diabolical human experimentation that has little or no relevance to the type of cancer research going on in the pharma industry.
(alternate definition of placebo: “a substance having no pharmacological effect but administered as a control in testing experimentally or clinically the efficacy of a biologically active preparation.”)
Chris
I’m interested in 2 comments here about CROs and their apparent immunity to the same approval processes followed by pharma or academic or research institutions (Bob and Matt). Ar eyou saying that CROs operate under different rules and approval systems - that’s not been my understanding. Is there more you could offer so I get it clear?
tks
Former pharma Marketing Exec
Nathan,
I do not mean to purposely mislead you, your comments are well intentioned and would fit well if I could give you more information.
Lets just say this; a couple of months into the trial he found out he was in the placebo arm of the trial. You will just have to trust me on this one.
I am interested on the comments about a CRO. These trials, regardless of who actually manages them, be it a CRO or a drug company still must go through the IRB’s and ethical committees of the hospitals - no? This is what is so disturbing. What will be interesting to find out is what information does the ethics committee get that allows them to allow the trial to go forward in their institution?
Interesting thread…