New medicines must be approved as safe, efficacious and of good quality before they can be prescribed. But authors of two recent articles in the British Medical Journal argue that governments should introduce new criteria to the approval process.
In Australia, ensuring the safety and efficacy of medicines is the responsibility of the Therapeutic Goods Administration (TGA). A drug is efficacious if it cures or alleviates the disease or condition experienced by the patient.
Pharmaceutical companies undertake clinical trials to determine whether a potential new drug meets the requirements for market authorisation. The final stage of the clinical trial process entails administering the drug to a large number of people. The effect on these patients is then compared to a control group given a placebo.
This type of trial is designed to establish whether it’s better for the patient to take the drug in question than not to do so. But it’s not possible in this type of trial to determine whether the new drug is better (and, if so, how much better) than already available medicines (or other therapies).
Raising the bar
The BMJ articles argue that regulators, such as the TGA, should raise the bar for marketing approval – a new drug should be approved only if it’s found to be at least equivalent to an existing alternative in terms of criteria such as efficacy and safety.
If no such alternative is available, then a new drug providing even a small positive effect may, of course, be valuable to patients. But it’s rare for a new medicine to address a condition for which no drug therapy was previously available.
The first of the articles notes that most new medicines provide only marginal benefits; of the 218 new drugs approved by the United States Food and Drug Administration (FDA) between 1978 and 1989, only 34 (15.6%) brought important therapeutic benefits.
The authors argue that pharmaceutical companies should be made to spend less on research and development in areas where several drugs are already available, and more in areas where the need is greater. This would require spending more on basic research, and less on trivial product modifications for the purpose of extending patent protection.
It would also be socially beneficial if less money was spent on marketing, which at present is a much bigger cost than basic research. The authors show that major drug companies spend only 1.3% of revenue on basic research to discover new molecules. More than 80% of funding for this type of research comes directly or indirectly from the public sector.
Marketing rules
Pharmaceutical companies would have to change their research and development priorities if they were required to demonstrate comparative efficacy when applying for marketing authorisation. The authors of the second article point out that the criteria for marketing approval have not changed much since the early 1960s, when the FDA was mandated to establish proof of efficacy and safety following the thalidomide calamity.
The pharmaceutical industry considers comparative efficacy a regulatory requirement detrimental to innovation. Clinical trials would become more expensive and fewer new drugs would be launched. But the authors of the first article show that innovation over several decades, as measured by the number of new drugs approved by the FDA has remained unaffected by regulatory changes.
Over several decades now, the FDA has approved between 15 and 25 new medicines annually. In the authors' view, there’s no problem of innovation in terms of the number of new drugs becoming available. Rather, the fact that new drugs typically don’t bring significant health benefits is the problem. Comparative effectiveness would provide an incentive for research and development to be focused less on disease areas already well served by many drugs, and more on those with poor treatment options.
Companies must to some extent already consider comparative effectiveness, at least in countries where public or private insurers pay a high proportion of the cost of medicines. The aim of health technology assessments undertaken when deciding whether new products should be listed on the Pharmaceutical Benefits Scheme (PBS), and similar assessments undertaken by agencies such as the National Institute for Health and Clinical Excellence in the United Kingdom, is precisely to determine comparative efficacy.
For payers, such as the PBS, it makes no sense to accept higher prices for a new product than for an already available alternative, if the existing product is only equally effective. Or even to accept paying anything at all if it’s not as good as the existing alternative.
Empowering consumers
The researchers argue that there “is a need to align the evidence needs of regulatory bodies, country level payers, and health technology assessment agencies” to ensure that as complete information as possible is available to prescribers and consumers. The absence of such alignment sometimes results in a drug becoming available for prescribing (being approved for marketing) while not eligible for reimbursement by the insurer (such as the PBS), causing confusion among both prescribers and patients.
Raising evidence standards for market authorisation to include comparative efficacy in Australia or the United States could also be beneficial in countries with less developed regulatory systems. In much of the developing world, patients not only have to pay the full cost of medicines themselves, but markets are typically swamped by large numbers of brands including many irrational drugs, causing confusion and harm.
Irrational products could more easily be weeded out if regulatory agencies, such as the TGA and the FDA, were to approve of new drugs only if they are equal or better than existing alternatives. And that would ultimately be good for everyone.
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
You should know that the Light and Lexchin paper is somewhat controversial, see
http://pipeline.corante.com/archives/2012/08/09/getting_drug_research_really_really_wrong.php
http://pipeline.corante.com/archives/2012/08/13/donald_light_responds_on_drug_innovation_and_costs.php
and
http://pipeline.corante.com/archives/2012/08/15/a_quick_tour_through_drug_development_reality.php
Craig Morton
Biomedical Research Scientist
Beat me to it Ian - 'somewhat controversial' was very polite of you.
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
I am nothing if not polite :-)
Rodger Kensen
Systems Analyst
Thanks for the reference and insight on this Ian, I must admit to being a skeptic about pharmaceutical companies but this is from a largely uninformed non industry background.
I guess the real issue that needs to be separated is that of the close ties between pharmaceutical companies and government via lobbyists in the US - but that is a concern about high level corruption and not the hard work that the majority of people in the industry do. Which probably equates to my views on religion, people who follow I get along with - it's the people in charge that have the power that concern me.
Monika Merkes
Honorary Associate, Australian Institute for Primary Care & Ageing at La Trobe University
Thank you Hans Lofgren for the article.
It saddens me to think about the many animals that have endured distress, pain and death in the course of producing these trivial product modifications.
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
What about all the people who were enrolled in Phase I, Phase II and Phase III clinical trials?
Also, 50.5% of all drugs were either significant or modest innovations, or accelerated ant-viral drugs. Less than half were 'slight or no-innovation"
However, a drug which is taken once a day rather than 3 times a day can be very important to patient populations (yet is not innovative). Also, a "me too" drug that is of a different chemical class but has no efficacy difference will allow patients…
Read moreCraig Morton
Biomedical Research Scientist
Of course you could save all those animals by predicting for us, in advance, which of these 'trivial product modifications' were going to be 'trivial', and which were going to be a major advance changing the way a condition is treated forever.
What, you mean that isn't possible? Dear me, we'll just have to keep on working really, really hard to try and find new cures for currently intractable or poorly treated conditions then and occasionally fail - because it's (as I just noted) really, really hard.
Rodger Kensen
Systems Analyst
My sister was trialled as part of one of these 'trivial product modifications' - while it was only an extra 3-6 months of living, barely 1-2% of the total of her life, my family and especially her 3 children appreciated one last Christmas together. The drug also wasn't even trialled on animals, although if it meant another 12 months of life you would not want to know how many animals I would have sacrificed to achieve it.
Sue Ieraci
Public hospital clinician
Editors: your caption under the photo states: "Clinical trials cannot help determine whether a new drug is better than already available medicines"
This is incorrect - and contradicts the text in the article that talks about some new drugs only providing marginal benefits - this is because they ARE compared with existing therapy. IN fact, it would be unethical to leave an arm of the study untreated if there is already an efficacious treatment.
There are many types of trials. A truly new therapy…
Read moreIan Musgrave
Senior lecturer in Pharmacology at University of Adelaide
Good catch on the caption Sue. Head to head comparison trials, while possibly not done as often as desirable, are indeed done.
Reema Rattan
Editor at The Conversation
This has been amended. Thanks for pointing it out.
Craig Morton
Biomedical Research Scientist
Except the amendment isn't correct either...
Clinical trials can and do demonstrate superiority to the existing standard of care - just do a quick search on clinicaltrials.gov and have a look at the hundreds of trials either in progress or completed that do exactly that!
http://clinicaltrials.gov/ct2/results?term=versus+%22standard+of+care%22
An acceptable caption *might* be, "Improving on current standard-of-care should have greater emphasis in clinical trial design." but even that is stretching things.
Sue Ieraci
Public hospital clinician
Craig is right - Reema - the caption is still incorrect. I don't know which point you are trying to make there, but there are lots and lots of trials comparing new drugs to previous standard therapy.
William Bruce
Artist
I saw Sicko by Michael Moore on TV last night....it touched on this issue and others. Very insightful and ighly recommended viewing.
It is up to Govt to "umpire" monopolies & ologopoles and PREVENT ALL entry barriers.....which include "regulatory costs".
Seems clear politicians can get "bought" by lobbyists & big business and then "collaborate with them" against the public interest.....they get "donations" (on both sides) and FAT JOBS after they get "unelected".....
With media in so few hands then NO adequate DEBATE......
Generic medicine OUGHT be an election issue.
Long live the Conversation and the free speech and venting of ideas it facilitates.
Adam n
other
The proposal to approve new drugs if they are better than existing ones is bad for competition. For example consider if there is an expensive drug on the market with patents to prevent others making a similar drug. If a company can make a drug that is slightly less effective but can be solved for significantly less than this is beneficial for those that can't afford the more expensive drug.
This article leaves one to wonder the link between the authors and drug companies with patents who would profit from such changes.
Having less effective products on the market may make it harder for the most effective medication to be prescribed. Other than this the proposed changes are likely to be against the public interest.
Adam n
other
*The proposal to approve new drugs *only* if they are better than existing ones
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
The cost of actually making a drug (with some exceptions) is only a small part of the actual price of the drug. The cost of developing the drug is sought to be recovered as well (which is rather high, no matter who you believe about development costs fro drugs)
Reema Rattan
Editor at The Conversation
But is that cost borne by the companies or the taxpayer through many years of research in publicly-funded institutions, such as universities?
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
The majority of the cost comes from the company sponsored clinical trials, the public funded research that helps find targets and possible chemical classes for drugs isn't cheap, but it pales into insignificance against the clinical trials necessary to take these drugs through to registration. See
http://pipeline.corante.com/archives/2012/08/15/a_quick_tour_through_drug_development_reality.php
for an indication of the processes involved
Luke Weston
Physicist / electronic engineer
For those who don't like "Big Pharma", you might imagine a hypothetical, somewhat "socialist" system as an alternative, where universities and state scientific organisations are funded by the government appropriately so that they shall take over all the same work, in research, development, testing, clinical trials, regulatory approval, manufacturing, and physician training in the use of newly available drugs, to deliver the same benefit to the public.
But there is no way in hell that a government would ever turn over money in basic science and R&D on the same scale of expenditure that the commercial pharma industry does. Politicians could never comprehend even putting that much money - the amount of money that is actually required to generate and validate useful products - in the same sentence as science.
Paul Savage
Theme Leader, Biotechnology at CSIRO
You might want to add some additional caveats to that Adam. It's also worthwhile to approve a less-effective new drug with a different mode of action, e.g. for antibiotics or antimalarials, because this will limit the spread of resistance. You might also want to approve a new drug that is *generally* less effective than existing therapies but is actually more effective in certain sub-populations. Several cancer therapies fall into this category. Likewise you might want to approve a drug that is less effective but has fewer or less severe side effects, and so on.
Since drug therapy is a complex, multi-factorial situation it's not always practical to declare a new drug *better* than existing ones.
Seán McNally
Market and Social Researcher
The idea of constantly raising the bar is one I support. However beyond the role of a regulator saying what is approved, several of mechanisms covered in the article (and the BMJ article as discussed in this article), I see as potentially counterproductive.
Firstly the notion that government should have a direct role in determining which area a company should invest is simply neither feasible nor desirable. The first hurdle is whose gov’t? If it just relates to R&D in your country then we…
Read moreLaurie Willberg
Journalist
"It would also be socially beneficial if less money was spent on marketing, which at present is a much bigger cost than basic research. The authors show that major drug companies spend only 1.3% of revenue on basic research to discover new molecules. More than 80% of funding for this type of research comes directly or indirectly from the public sector."
It's telling that many commenters here have completely ignored the most important aspect of this article.
The focus of the pharmaceutical industry is primarily on stock values and profits.
The cat is out of the bag, folks. The drug industry is in a shambles, and deservedly so.
The public sector should not be funding drug company "research". The more people who become aware of this ridiculous scam the better.
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
The 1.3% figure is also very, very debatable. But also remember clinical trials cost way, way more than basic science ( and the preclinical toxicity and efficacy screening). Any thing that becomes a successful drug will only have a fraction of it's cost as basic research by default. Again, read these links for an overview:
http://pipeline.corante.com/archives/2012/08/09/getting_drug_research_really_really_wrong.php
http://pipeline.corante.com/archives/2012/08/13/donald_light_responds_on_drug_innovation_and_costs.php
and
http://pipeline.corante.com/archives/2012/08/15/a_quick_tour_through_drug_development_reality.php
Luke Weston
Physicist / electronic engineer
Glad I'm not the only Derek Lowe fan around here. He's got to be amongst the world's longest-running, and best, serious science bloggers.
Reema Rattan
Editor at The Conversation
Hello all,
Hans is abroad and has asked me to point out that the BMJ articles are linked in the article above.
for good measure, here are the links again:
http://www.bmj.com/content/345/bmj.e4348
http://www.bmj.com/content/345/bmj.e4261
Craig Morton
Biomedical Research Scientist
Reema you still need to correct the caption for the opening image - it's not a matter of opinion as to whether the current caption is misleading! Clinical trials are OFTEN used to demonstrate 'whether a new drug is better' than the standard of care as well as 'how much better'. And they also show if a drug is NOT better - a news release I received in my email today, for example, states:
"Effient misses Phase III endpoint vs. Plavix
Read moreDaiichi Sankyo Co. Ltd. (Tokyo:4568; Osaka:4568) and Eli Lilly…
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
Craig is right, the caption is not correct. For example, comparator trials to determine if one antibiotic is better than another is routine for new antibiotics. http://www.ncbi.nlm.nih.gov/pubmed/21956949
cancer therapies are also usually against standard of care.
How about this?
"Clinical trials to determine whether a new drug is better (and, if so, how much better) than already available medicines should be more common."
(just as an aside, here are the results of a simple off the top…
Read moreIan Musgrave
Senior lecturer in Pharmacology at University of Adelaide
Ah ha! I see the problem, it's this sentence in the main article.
"But it’s not possible in this type of trial to determine whether the new drug is better (and, if so, how much better) than already available medicines (or other therapies)."
What this means is that PLACEBO controlled clinical trials are not helpful, not clinical trials **per se**. COMPARATOR controlled clinical trials (where the drug is tested head to head with a currently used drug, as in my and others examples above) are perfectly capable of telling us this (and do). The wording the author uses is slightly ambiguous, and he doesn't mention comparator based clinical trials directly (although they are implicit in his following paragraph).
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
Thanks for reposting the links again. For what it's worth, in 2011 the FDA approved 30 new drugs. Of these 11 (36%) were first in class compounds. Several, while not first in class, were small molecule drugs aimed at cancer specific growth pathways (in most of these cases a core molecule has been modified to hit a unique target or targets in the pathway, so are not really me too compounds).
I looked at 4 drugs that could be reasonably called "Me Too" compounds, one, for treating blood pressure…
Read moreCraig Morton
Biomedical Research Scientist
Fine - the caption is still both wrong and misleading! :)
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
What do you think of my suggestion?
"Clinical trials to determine whether a new drug is better (and, if so, how much better) than already available medicines should be more common."
Craig Morton
Biomedical Research Scientist
Definitely an improvement, but still somewhat misleading. Where a standard of care exists the majority of clinical trials are already structured to include (if not entirely be based on) comparative data. So 'more common' is the bit I dislike. My attempt was "An acceptable caption *might* be, "Improving on current standard-of-care should have greater emphasis in clinical trial design." but even that is stretching things." (see above).
And your point about exactly what one means by 'superiority…
Read moreIan Musgrave
Senior lecturer in Pharmacology at University of Adelaide
I agree whole heartedly, but I'm thinking of how to rewrite the caption so it is factually correct but with the authors intent intact, regardless of the nuances (realities) that we see.
With the author not in a position to discuss this at the moment, we should ask for the minimum possible changes.
Reema Rattan
Editor at The Conversation
Wow! So much attention to a caption. Apologies all for the mistake (twice!) and for not getting to it sooner in the day.
Let me know if the very neutral one suits.
Reema Rattan
Editor at The Conversation
No one commented on the excellent image that took ages to find though...
Ian Musgrave
Senior lecturer in Pharmacology at University of Adelaide
Hey, we're scientists, we get very anally retentive about things like captions (especially when they imply to opposite of the actual data). Just spent the last two days redoing a single figure for a paper (okay, not all 48 hours was spent on this, but certainly more time than spent discussing this caption).
The image for this article was really cool though :-)
Craig Morton
Biomedical Research Scientist
Much better. Thanks.
As Ian noted, getting captions (and figures) right is one of those things that can end up taking way more effort than seems rational, until you realise that some people will skim an article and that's the only bit they'll read properly.
Oh, and the images are all lovely...
Reema Rattan
Editor at The Conversation
Thank you both for your kind words. Look out for Ian's excellent article on aluminium in anti-perspirant next week. And email me on reema.rattan@theconversation.edu.au if would like to discuss the possibility of contributing articles to out page.
Sue Ieraci
Public hospital clinician
Much better - thanks Reema.
Of course the image is powerful, and, sitting at the top of the story, draws the reader to the caption as the first message delivered about the story. All the more reason to get it tight - otherwise it sets the wrong "spin" on the whole article from the outset.
(The science of editing)
Sue Ieraci
Public hospital clinician
A question for the author: would you single out pharmaceutical manufacturers in being subject to regulation regarding what products they are allowed to develop and how they break up their budget between R&D vs marketing?
What about other industries? What about the enormous CAM industry? SHould Boiron (the multinational "manufacturer" - diluter - of homeopathic "remedies") be obliged to spend more on R&D and less on marketing? SHould they be obligged to close down altogether if their products are useless?
Jon Cylus
Research Fellow
Thank you Dr. Lofgren for this great article which describes some of the work we've been undertaking at the London School of Economics and European Observatory on Health Systems and Policies. I'd like to direct your attention to a blog we recently wrote on this same topic.
http://blogs.lse.ac.uk/healthandsocialcare/2012/08/17/raising-the-bar-does-stricter-market-authorization-regulation-deter-pharmaceutical-innovation/
As well as to a brief interview (around 23 minutes into the program) with…
Read moreIan Musgrave
Senior lecturer in Pharmacology at University of Adelaide
Thanks for the clarification Jon, however:
"We believe that raising the evidence threshold for market approval of drugs in therapeutic areas where there are already lots of effective drugs will incentivize manufacturers to invest in areas where there are fewer comparators and greater unmet need."
Not convinced here. No one will start drug development in a crowded therapeutic area unless they believe they have a drug that will out compete others in an already crowded market. After all, who needs yet another angiotensin converting enzyme inhibitor, no one will prescribe a new one over standard of care unless there is some good reason to, and unless you can supply a putative good reason *before* you commit your company to spending around billion dollars it's not going to be developed.
Cancer drugs may be a special case because of the emotion that surrounds cancer, but you can hardly call the cancer field replete with effective drugs.
Yoron Hamber
Thinking
Hans "The authors show that major drug companies spend only 1.3% of revenue on basic research to discover new molecules. More than 80% of funding for this type of research comes directly or indirectly from the public sector." Is what I find really unsavory here.
We seem to work by 'mouth to mouth' still, maybe because people are lazy? Even though the Internet have existed for quite some decades. And the advertising firms use it for telling their clients that without commercial advertising the…
Read moreIan Musgrave
Senior lecturer in Pharmacology at University of Adelaide
Those figures are very misleading (and I say this as a publicly funded researcher trying to help develop new therapies for diseases).
1) The accounting of "basic R&D" in these studies is somewhat controversial, and often ignores a lot of the medicinal chemistry needed to develop drug candiates.
2) Basic R&D costs a LOT less than clinical trials ( a single trial can cost well over 10 million dollars, and you need a few of them), basic science R&D will * always* be much less than clinical development.