Showing posts with label top selling drugs. Show all posts
Showing posts with label top selling drugs. Show all posts

Wednesday, May 24, 2023

Top Selling Drugs, Conflict-of-Interest and Market Hype

 



This post is another public service announcement to the criticism psychiatric medications in perspective. It is an essential part of the continuous production of antipsychiatry rhetoric because it must be.  If you are arguing that there are no such thing as psychiatric disorders – you do not need any treatment for them. On that basis overprescribing easily occurs because any prescribing is overprescribing. There are mixed agendas on claims that antidepressants in general cause increased number of suicides and aggressive behavior. But the most significant rhetoric has always been that there are massive conflicts of interest in psychiatry due to payments or relationships with the pharmaceutical industry. In a rare piece of special interest politics, a US Senator made these claims. Now that we have a database, it is easy to show that psychiatrists in general are not even close to the top when it comes to physician payments from the pharmaceutical and medical devices industries and in fact that most physicians have no significant conflict of interest.  This post specifically is about the top 15 selling drugs in the period 1990-2021, and where drugs typically prescribed by psychiatrists end up on that list.

I will qualify this by saying as I have many times in the past, that the only medication that psychiatrists prescribe more of than any other medical specialty is lithium.  Practically all other classes of psychiatric drugs are prescribed in greater amounts by primary care physicians, pediatricians, and an ever-increasing number of non-physician prescribers primarily nurse practitioners and physicians assistants-certified.

The methodology for this post is subject to several limitations.  First it depends on word and term frequencies counts from search engines that look at the popular, press, academic journals, newspapers, websites, and books.  By comparison the Google NGRAM search looks only at frequencies in their book collection. Algorithms are used to determine relevance and importance – but the weighting of the algorithm is not available so the actual search is a black box – but consistently applied.  It does not count word frequencies in the non-print media and in the US that would include direct to consumer advertising for many of these drugs. A second limitation is that all the counts obtained here were for the years 1990-2021 in aggregate. No curves were generated by year like the ones available in NGRAM. Sometimes a verbal estimate was available like “most of these references occurred in the past 10 years”.  A third limitation occurred when searching for terms like “antidepressant overprescribing” the search engine went from Google Scholar to Lexis-Nexis even though I had no direct access to Lexi-Nexis.  I have a request pending for that access to see if I can confirm the results listed here, especially because much of this search required an artificial intelligence search engine (Google Bard).  If I cannot get direct access to Lexis-Nexis I will attempt to check the results with a second AI search engine.

My goals were to compare the general publicity with the negative publicity of the top 15 selling medications of all time.  When I looked at that list – only one of the 15 medications was a psychiatric medication and that was olanzapine (Zyprexa). For that reason, I decided to extend the comparison to all antidepressants that were discovered during the same years (1990-2021).  During that time there was continuous criticism of psychiatrists that was primarily antidepressant based. The suggestion was that all psychiatrists were in lock step with Key Opinion Leaders (KOLs) and prescribing whatever Big Pharma wanted them to irrespective of patient need or diagnosis. This is obviously an absurd criticism but it was taken very seriously for the better part of two decades. An associated criticism was that clinical trials of psychiatric medication were permanently tainted by the same conflict of interest.  Psychiatrists were mere puppet prescribers for the pharmaceutical industry.  Like most dichotomous arguments there were vehement supporters of both poles but very little discussion of the reality that psychiatrists are the treatment providers of last resort dealing with difficult problems and they just happened to have the most expertise in prescribing these medications. These arguments also ignored the fact that psychiatrists are taught to critique literature and apply it to practice and that this life-long skill makes it doubtful that anyone prescribes a medication just based on the word of a salesman. All the attacks on monolithic psychiatry ignored what was potentially the most significant cause of antidepressant prescribing – checklist-based diagnoses popularized by managed care and electronic health record systems. No comprehensive psychiatric evaluation – just a cutoff number on a checklist. And yet no criticism of managed care companies doing this?  I have also not heard the same level of criticism for telepsychiatry services that are currently advertising their antidepressant prescription services.

 

Table 1. Top 15 gross selling medications of all time:

Medication

Sales

(Kiplinger 2017)

Sales

(Bard 2023)

Word Frequency

References

1990-2021(1)

Overprescribing by drug references1990-2021 (1)

Lipitor (atorvastatin) 2001

$150 B

$130B

38M

20,000

Humira (adalimumab) 2008

$109 B

$240B

17M

1,000

Advair (fluticasone/salmeterol) 2000

$95.7 B

$350B

12M

1,000

Remicade (infliximab) 1998

$90.3 B

$100B

2.5M

100

Plavix (clopidogrel) 1997

$83.7 B

$55B

13M

10,000

Rituxan (rituximab) 1997

$81.6 B

$60B

1.3M

100

Enbrel (etanercept) 1998

$81.2 B

$100B

5.7M

300

Herceptin (trastuzumab) 1998

$70.5 B

$140B

1.2M

100

Avastin (bevacizumab) 2004

$67.4 B

$100B

1.5M

100

Nexium (esomeprazole) 2001

$61.8 B

$150B

7M

20,000

Lantus (insulin glargine) 2000

$61.6 B

$100B

1M

1,000

Diovan (valsartan) 2005

$60.8 B

$100B

2M

200

Zyprexa (olanzapine) 1996

$60.6 B

$55B

3.5M

1,000

10,000 for APs

Crestor (rosuvastatin) 2003

$56.9 B

$125B

1.5M

20,000

Singulair (montelukast) 1998

$47.9 B

$50B

200K

100

 

Table 2. Antidepressants approved 1989-2021

Antidepressant

Total Sales

Literature references (1)

Overprescribing by class 1990-2021 (1)

Wellbutrin (bupropion) 1985

$40B

2.5M

100,000

 

Prozac (fluoxetine) 1987

$32B

22M

Zoloft (sertraline) 1991

$50B

16M

Paxil (paroxetine) 1992

$40B

13M

Effexor (venlafaxine) 1993

$70B

10M

Celexa (citalopram) 1998

$50B

12M

Lexapro (escitalopram) 2002

$40B

8M

Cymbalta (duloxetine) 2004

$35B

14M

Viibryd (vilazodone) 2011

$1.5B

3M

Trintellix (vortioxetine) 2013

$2B

1M

1.  Lexis-Nexis search via Bard.

 

Table 3.  Approximate Number of Prescriptions

Drug Class

Estimated Number of Prescriptions

Statins (atorvastatin, rosuvastatin)

200M worldwide

Antidepressants (table 2 plus earlier ADs)

150M worldwide

Monoclonal Antibodies

Millions

PPIs (esomeprazole)

17.9M in 2008

Clopidogrel

18M in 2016

Valsartan

18M in 2016

Advair

2.5M worldwide

Etanercept

2.5M worldwide

 

A couple of qualifiers before comments.  First there is no organized registry or pharmacosurveillance system for basic monitoring of any prescriptions in the United States and in most countries. Total prescriptions and sales in the US have always been proprietary data.  It typically involves sampling local pharmacies and then extrapolating those sales to the larger population. Practically none of that data is available to the public but it occasionally shows up in articles in both the popular and professional press. Second, the proxies chosen here for comparing drug classes including the number of times a particular drug or term is mentioned in the popular and professional literature is also approximate because these words can be used frequently in the same paragraph and the context is not apparent – the words could be used in both positive and critical contexts. The “overprescribing” term closely paired to the drug name was chosen as a proxy for critical articles – but even then, the level of criticism and whether it was appropriate or not is an open question.  Looking at the general number of people exposed to each drug class it is reasonable to assume that 5 of the drug classes – statins, antidepressants, PPIs, clopidogrel, and valsartan have probably all been prescribed to about 200M people. The immunological drugs including the monoclonal antibodies and etanercept have been prescribed to many less probably somewhat less than 10M people. The Advair number seems very low to me since it has been around for 23 years and was able to continue patent protection beyond the expiration date not for the medication but the unique dispenser. 

I have the following observations based on what is available:

1.  Despite an overall increase in antidepressant prescriptions – new antidepressant prescribing and revenue is low.  This is probably due to the abundance of generic antidepressants and associated rationing of access to newer antidepressants by managed care companies (MCO) and pharmacy benefit managers (PBMs). My only interest in revenue is as a proxy for total number of prescriptions. Looking at the total revenue over years of availability in table 2 – antidepressants generated about $1-2B per year.

This is the downside to the antidepressant prescribing conspiracy theory.  If the business model was as simple as influencing mindless doctors there would not be such a drop in revenue.  There would be a never-ending revenue stream available just from that manipulation. The conspiracy theory fails to account for the regulatory model that rewards innovation with time limited patent protection but even then there are limits, in this case an abundance of generic drugs due to expired patent protection.

The conspiracy theory also fails to account for the fact that these patterns are well known and have happened in the past. When I was an intern one of my attendings commented that it was ironic that pharmaceutical companies were making billions off of indigestion with H-2 blockers while there was hardly any research being done on malaria - a disease that was killing a million people a year at that time. When the H-2 blockers (cimetidine, ranitidine, famotidine) became generics, proton pump inhibitors took their place in the billion-dollar profit cycle.  With the current regulatory landscape this cycle will continue to repeat.  At any given peak in the cycle it may appear there is a conspiracy to increase Pharm profits – but it appears those suggestions only happen when psychiatric medications are involved.

2.  The current top selling drugs take the approach of selling to very large populations or selling very expensive agents to smaller populations. Atorvastatin as an example generates about 3 times a much revenue per year as an antidepressant targeting about the same population size.  I have some insider information about atorvastatin and its manufacturing.  I was told by a chemist that at the time of its original manufacturing it was the most expensive tablet every produced and that cost was $1.00 per pill.  Today it is possible to get a 90 day supply of 10 mg tablets for $3.44 to $6.44 and the generic manufacturers are still making money.

3.  One of the rationales for regulatory protection of patent protection is the high cost of research.  Is there any evidence this applies to the current landscape of psychiatric medications?  At least one industry analysis expects slower than expected growth in “mental health therapies” but much greater growth in immunological therapies, cancer therapies and obesity therapy.  All would appear to be driven by current profits in these areas.  The current down cycle in psychiatric research may also explain the attempts to resuscitate hallucinogens and psychedelics for this application. There has long been the outcry that the only reason these drugs have not been adequately researched was their classification as Schedule I compounds – but the research so far has not been impressive.

4.  Given the limitations, the most striking number in the tables are the number of “antidepressant overprescribing” articles in the popular and professional literature.  That number (100K) exceeds the total number of overprescribing references in Table 1. by 25%.  There is not much granularity there but when taken in combination with statements seen in both the popular press and research literature it may confirm what has been known for a long time – psychiatry is by far the most criticized specialty whether that criticism is rational or not.

The cycles of feast and famine in the pharmaceutical industry are always the product of innovation, marketing, and politics just like any other capitalistic enterprise in the US. There is an opportunity to do immense good and we have just seen that happen with the vaccines and medications invented to stop a pandemic. Even the best possible treatments have side effects and sometimes very bad side effects. That is the expected cost of treating any diverse biological population. Psychiatrists and the medications they use are not better than that biological constraint – but they certainly are not worse.

 

George Dawson, MD, DFAPA

 

 Supplementary:  I would like nothing better than to have more accurate information about top selling drugs and who is prescribing them. If you have available sources send them to me or post the links here.  I can reanalyze the data if it becomes available. 

Graphics Credit: Many thanks to Rick Ziegler for allowing the post of his photo.

 

References:

 

1:  Brumely J. The 15 All-Time Best-Selling Prescription Drugs.  Kiplinger.  December 17, 2017

2:  Urquhart L. Top drugs and companies by sales in 2018. Nature Reviews Drug Discovery. 2019 Mar 12:NA-.

3:  Urquhart L. Top companies and drugs by sales in 2019. Nature Reviews Drug Discovery. 2020 Apr 1;19(4):228-9.

4:  Arrowsmith J. A decade of change. Nature Reviews Drug Discovery. 2012 Jan 1;11(1):17.

5:  Moorkens E, Godman B, Huys I, Hoxha I, et al. The Expiry of Humira® Market Exclusivity and the Entry of Adalimumab Biosimilars in Europe: An Overview of Pricing and National Policy Measures. Front Pharmacol. 2021 Jan 8;11:591134. doi: 10.3389/fphar.2020.591134. PMID: 33519450; PMCID: PMC7839249.

6:  Aitkin M, Kleinrock M.  Global Use of Medicines 2023: Outlook to 2027. January 2023.