FDA Is Approving Fewer New Molecular Entities
24 CommentsBy Ed Silverman // March 11th, 2008 // 2:20 pm
Cutting to the chase, NME approvals are “on pace with a miserable 2007,” writes Jim Kumpel of Friedman Billings Ramsey, in an investor note this afternoon. Through the first two months of this year, the FDA has approved 14 New Drug Applications, which is up from 7 last year and an 11-year average of 11. But there was only one NME approved, which is the same rate as 2007, but below the 11-year average of two, he writes.
Why the slow pace? Kumpel posits that the FDA Amendment Act of 2007, which included PDUFA reauthorization, required rapid implementation of several key initiatives, and overwhelmed the FDA review staff. And he notes that John Jenkins, who heads the Office of New Drugs, sent his staff a memor authorizing them to miss PDUFA deadline by up to two months if staffing constraints continue.
“We believe the staffing concerns for FDA reviewers will remain for the next few years,” he writes. “Even though PDUFA IV increased the fees pays to the FDA and authorized the agency to hire an additional 205 people, the roles will take time to fill, and training a medical officer can take up to three years.”
Jack2
Anyone know the one new NME for 2008 off the top of their head?
Tom
Jack2 - there was an orphan drug approval two weeks ago http://www.fda.gov/bbs/topics/NEWS/2008/NEW01801.html
Tom
Also a newly approved HIV drug - this one looks like the NME http://www.fda.gov/bbs/topics/NEWS/2008/NEW01783.html
Dan
There have been relatively very few new molecular entities over the years. Yet there has been an acceleration in ‘me too drugs, which involves only tweaking what once was a new molecular entity. Orphan drugs are typically not a primary objective, at least with big pharma, as they continue thier membership in lucrative disease states, which mainly contain meds that delay the progression of disease, such as cardiovascular or diabetes. Innovation is minimal in this corporate enviornment.
Nathan
Dan,
You are mistaken. A “me too” drug IS a new molecular entity. Typically a “me-too” drug is a related (or unrelated) molecule that hits the same target. As I’ve pointed out previously, “me-too” drugs are not bad. They increase competition among drug companies, thereby lowering prices. Different compounds have different side effects, even though they go after the same target. Therefore, one drug may a significantly better overall profile than another even though at first glance they are “me-too” drugs.
I would also object to your characterization of “minimal innovation” taking place in pharmaceutical companies. More innovation is probably taking place at biotech companies than at big-pharma. However, the failure rates for compounds in biotech is much higher. They are willing to take on higher risk projects. However, most big companies try to keep a balance of high risk and low risk projects. There is always innovation taking place — but the true innovation is always kept in check by the development of “lower risk” (often “me-too”) drugs.
Justice in Michigan
“Me too” is, as far as I know, not a scientific category, so we are talking about a range of different things. E.g.,
There are “extended release” versions of a drug which I don’t think anyone would claim are NMEs.
There are drugs that change the amount of active ingredient or add a different preservative (like Alphagan P eyedrop) which does not recreate Brimonidine Tartrate, and thus which I don’t think anyone would call an NME.
There is metabolites of existing drugs or L/D shifts which some might argue are new.
And a range of other tweaks and turns.
There is a zone in which when an NME becomes an NME is in the eye of the claimant.
Personally, if there is evidence of different interactions with other drugs (like Nexium v. Prevacid, for example), or similar hard findings, that would be one (of other) good criteria from my perspective.
Atlex
Nathan is correct. For some reason, there are two versions of “me-too” drugs. Within the industry, “me-too” drugs are new molecular entities that are closely related (pro-drugs, metabolites, etc.); examples include Nexium (related to Prilosec) and Clarinex (Claritin).
Industry gadflies, such as Marcia Angell and Jerry Avorn, call any product that is not novel in a class a “me-too); for instance, in their definition, Mevacor is innovative and all of the other statins (Zocor, Lipitor, Crestor) are “me-toos.” The problem with the latter is that these follow-on products serve a valuable role both clinically (providing clinical alternatives) and economically (holding down price–not necessarily at the retial level, but in negotiations with payers). From a clinical perspective, follow-ons within a class can be critical–many times they improve the side effect profile, provide grwat efficacy, or treat patients who might be resistent to the initial product.
Bob Freeman
Atlex and Nathan, I agree with your comments about the value of incremental innovation. To add to the discussion on economic competition, Lichtenberg at Columbia has studied competition among patented drugs and concluded that the economic gains to the consumer are actually of a higher magnitude than those from patent expiration. I don’t have a citation but a Google Scholar search on “creative destruction and Lichtenberg” should yield citations.
The gain in consumer welfare is due to elimination of monopoly profits when new entrants enter the therapeutic area. In other words, the patent-holder of the first in class can only charge monopoly profits when other patented drugs in that class have yet to be launched.
Jack2
I want to defend companies that make “me-too” drugs under the widest definition - the definition where Lipitor ranks as a me-too.
These drugs take 10+ years to develop. So Pfizer didn’t look at Zocor and say, we should make a statin too, let’s get that started, the way Ford can look at GM and say “we need an SUV with 3 rows of seats too” or something like that. They started making Lipitor and looking at HMG-CoA reducatase inhibitors not only before Zocor reached the market, but probably before they even knew Merck was also looking at HMG-CoA reductase inhibitors. Plus a lot of me-too’s may work by a similar mechanism but provide different trade-offs. The benzodiazepines possess different kinetics - which makes them suited to different purposes. The atypical antipsychotics (likely) possess different trade-offs in efficacy and tolerability, and different specific safety risks.
Dan
No, I am correct. A new molecular entity is free from existing moieties, or chemical molecules. ‘Me too’ drugs are, conversely, based on these moieties, and are tweaked slightly to gain promotion rights. Same tactic is utilized to convert such drugs as claritin to clarinex or prilosec to nexium.
Dan
The interesting comments associated with this post are a matter of linguistics. If a drug is primarily the therapeutic equivalence of an existing drug, it is a ‘me too’ drug. Yet admittingly, I’m not a doctor. Yet those who agree with my statements are doctors that have authored books on this subject.
Justice in Michigan
The question with which I am left for folks in industry (or others in the know) is whether there is _any_ drug that you would call a “me-too drug” but that is _not_ an NME?
nathan
Justice,
During my time in industry, I have *ALWAYS* heard people refer to a “me-too” drug as NMEs. A new indication for an existing drug is called “life cycle management”. That is completely distinct from a “me-too”.
I will STRONGLY reiterate what Jack2 says: “Me-too” drugs still take upwards of a decade to design and move through clinical trials. It is not fair to characterize these drugs as “not innovative”. Most companies are going after the same targets. Here’s an example dear to my heart: Currently all the major companies are going after prostaglandin receptors for inflammation. Right now, this is a wide-open field, ready for an innovative new drug. However, 10 years from now (when all the compounds simultaneously reach the market) people will be characterizing them as “me-too” and “not innovative”. As scientists, we build drugs based on what is being reported in the current scientific literature. The problem is that we all read the same literature and we all come up with very similar ideas. In the end, this leads multiple companies to develop very similar drugs….
Justice in Michigan
Thanks, Nathan. I am not a “me-too” critic. As noted on another thread, I have used Prevacid. I did so because the other PPIs had interaction issues for me. So glad Prev an option.
Atlex
Justice, I’m pleased that your personal experience has demonstrated the need for follow-on drugs in a class. There are many academics out there (eg, Angell) who would disagree with you. As a pharma supporter, where I criticize the industry is in the development of products witht he same or near-same ME that offer no clear advantage. I can understand the development of a 1x/day version of a TID drug–increased compliance has value. This can be accomplished through a different delivery mechanism (timed release, eg.) or via a related chemical entity (pro-drug or metabolite). What drives me nuts is the development of near-same MEs that offer little or no added value–eg, Nexium and Clarinex. These may offer short term sales for the manufacturer, but they hurt the industry in the LT.
Former pharma Marketing Exec
Nathan and Justice,
This is good dialog about the issue of “Me too” - Nathan I can understand your frustration. And although I know you are not a fan of what I have said before. The example you share with us here on this thread highlights the point I was bringing up on the other thread. If there was some sort of way to communicate with one another through a government entity wouldn’t the patient population be better served if the information was shared and managed in a way that would allow for a some variations of a treatment for a given disease to be brought to market and incentive be given to help focus research into other areas.
I agree that two or three slightly altered molecules drive competition and the patients are helped because of the pricing issues. But lets be clear on this as well, in marketing we study the prices of products in the same category and we honestly bring our product prices to match what the market will bear and that doesn’t mean we are going to do much to bring the price down. Yes, there is some collusion amongst us, whether we admit it or not.
Today’s system really needs an overhaul. It adds way too much cost to the system and then we wind uo having to continue putting too much of an emphasis on marketing and sales which inevitably takes away from innovative research.
Nathan
FPME writes:
“If there was some sort of way to communicate with one another through a government entity wouldn’t the patient population be better served if the information was shared and managed in a way that would allow for a some variations of a treatment for a given disease”
There IS communication between us already. We all know we are working on the same targets because we are all publishing about the same targets and we all go to scientific meetings and present work about the same targets. We learn from one another AND compete with one another. Remember, the drugs we are publishing about today will not be on the market for another 5-10 years. We don’t need a government agency to tell us that there are significant R&D overlaps between companies – we know that already. What to DO about those overlaps is a different question… It sounds like you want to force companies to eliminate or minimize those overlaps. My opinion is that the government should not be in the business of dictating the use of private R&D money.
I also take issue with your characterization of “me-too” drugs as “slightly altered molecules”. Sometimes that is true. If I’m struggling with a particular series of compounds, I might look at a competitor’s patent and make a few intelligent “tweaks” to their molecules and start testing out those compounds myself. However, more typically we are working on completely independent series of molecules. In the end, they may have similar properties simply because we all have similar objectives — but the molecules themselves were developed and optimized largely independently from one another.
Former pharma Marketing Exec
The point is Nathan, there are overlaps and that needs to be fixed. Do I think industry will fix them themselves - no I do not…Dialog, Dialog, Dialog I really do not want to “force” anything other than finding a way to make the system work better, overcome the overlaps without penalizing the innovators and researchers.
You shouldn’t take issue with my characterization of “me too” drugs, you admit that this does happen. The point is those are the ones I am looking at, these can and should be highlighted as un-necessary. Read my words carefully, I did not say this is an arbitrary issue.
Bob Freeman
Another way incremental innovations enter the market(me toos, if you prefer) is through in-licensing from Japanese companies. For many years Japanese companies thrived in Japan by tinkering with molecules–the regulatory and reimbursement systems encouraged this practice. Since Japanese companies didn’t have a significant marketing presence in the US, it was easy to out-license the North American rights to a pharma company that was strong in the US. Justice, your Prevacid was in-licensed from a Japanese comapany (Takeda) and sold through a separate joint venture (TAP) formed between Takeda and Abbott.
As an aside, I wonder how the “new” model of letting biotech companies take the risk of early stage drug discovery and then in-licensing the technology (or acquiring the company) will affect drug prices in the future, since royalty payments will be reflected as a cost of goods. The record high prices for deal-making will have to be factored in at some point.
Justice in Michigan
Yes, Atlex, we agree. The last sorts of examples you give - which are really a third category - are what drive me crazy as well.
As for Angell and others, there has been a bit of a “me too” phenomenon there as well - particularly in many of the pop critiques that have followed on. There is also work that is new and does, indeed, deserve serious attention.
techdiligence
This has been a great series of comment, far better than most threads. As a former development chemist from large pharma I recall that the FDA had a definition for NCE (new chemical entity); “a chemical structure not previously marketed for human therapeutic use.” I assume this definition remains for the NME label.
The me-too issue is well summarized by Nathan in his several posts. The existence of these has nothing to do with one company looking at a new, successful drug and then trying to copy it; it is the result of multiple companies making the same decisions 10 years (or more) in the past, and having technical and clinical organizations that have the same (high) level of ability since they are hired from the same pool of talent. No one should be surprised that two organizations going after the same biological target actually produce the same drug, perhaps within months of each other.
And me-too drugs do serve a real, clinical purpose. My wife cannot tolerate atenolol but metoprolol is fine. As a chemist, I can say that the structures of these two molecules do not show sufficient difference to make me think there is a huge intellectual step to get from one to the other, and I am surprised only that the initial patent (on atenolol) did not cover the metoprolol structure - but I say this 40 years after the fact. Thus, I can suggest only one practical mechanism to decide what is a me-too drug and determine that it is unnecessary; prove safety and efficacy, then put it on the market and let the decision be made there - by the people actually taking the drug.
The issue posed by Atlex will hopefully recede as clinical work becomes more thorough. I cannot speak for Nexium, but the Clarinex molecule is a metabolite of Claritin, and the current patent laws do allow this to be claimed as a new material. The only way to avoid this (in reality) is to test for metabolites and their biological activity during both discovery and development of the drug. This is done now, but is not easy to predict until there are clinical results, and then it is too late to change (although one could still patent).
Nuria Homedes
Could someone clarify why the FDA page lists a much higher number of NME per year? see link below
http://www.fda.gov/oc/history/NDAapprovals.html#table
Thanks
Jun
To Nuria: I think this story and its data are bogus. I do research on orphan drugs. If you read the title of the graph, it says “… through February.” I think they are only showing the first two months of every year. There is no doubt that FDA has approved more NMEs and NBEs per annum. As for NMEs being a small proportion of NDAs, this is a no-brainer, because all types of applications go through as NDAs, such as new formulations, new manufacturers, new labeling etc.
CMC guy
Good discussion and will jump in late with a few observations. Nathan, Jack2 and Atlex are correct about the technical definition of NME (or older NCE tag) as any change in structure would be classified this way (so JIM answer NO in my experience). However techdilligence point about metabolites (and I’ll add prodrugs) is that even though we might consider only near new-NMEs they can behave differently.
As noted “me toos” are necessary because don’t find found theperfect drug(s) due to individual responses (positive and negative) to different compounds in spite of same target or structural similarities. Nathan correct about people chasing same targets at different shops as “ideas” occur simultaneously because people read same papers and go to same conferences (and have much the same training). Usually by time you find out other companies working on same thing the investment is too big and likely requires greater costs as race begins. I think also tied to “blockbuster” mentality as limits possible areas of effort willing to get into.
Bob’s question of drug price with biotech discovery sources I would suggest not much impact since FPME notes prices largely determined by what market will tolerate (which may force down in future). It may help control early development costs a bit but biotechs are often even less efficient that big pharma in R&D and generally can’t do later steps well at all. The smaller companies are less afflicted with blockbusteritis so that help widen fields of investigations