Thursday, June 1, 2023

The Neuroscience Center

 




Back in the 1990s and early 2000s I was part of a Memory Disorder Clinic that eventually became a Memory Disorder and Geriatric Psychiatry Clinic. When I joined there were 3 physicians a neurologist, a geriatrician/internist, and myself.  We also had a social worker and an RN. We did detailed evaluations of cognitive problems of people in people ranging from their late 40s to their 90s. We saw a significant number of people with brain injuries and probably the most people with hypoxic brain injury that I had seen anywhere. We had multidisciplinary conferences and met with families in those conferences to discuss our recommendations. We also offered some research protocols and tacrine – the first centrally acting acetylcholinesterase inhibitor (ACEI) until safer medications from that class became available.  We saw and followed a unique group of people with chronic delirium who we followed until they improved.  I was developing a resource for people with aggression and dementia and thinking about how to do telepsychiatry at that facility for rapid access.  At the time there were no facilities that dealt with that problem and it typically resulted in discharge or prolonged hospitalization.  Since most of those patients were admitted to my acute care unit it would also decrease inpatient utilization. We had a small number of examination rooms, a nurse’s office and a shared conference room in a large medicine and medical specialties clinic.  Nothing fancy - I went there for my own care but I may have been seeing it through the rose colored glasses of an altruist. After all - we were on a mission - all of us. We had a good referral base and many primary care physicians liked our service, referred patients to us, and consulted with us by email or phone.  At the time we were all part of a private multispecialty group in a Level I trauma center – dedicated to provide care to anyone in our metro area.

Flash forward a few years. We have been acquired by a managed care company. The details of that acquisition were never clear to me but it did not take long to impact the clinic.  The inpatient neurology service was eliminated.  They were not a source of referrals for us – but that change had an impact on my neurology colleagues. I had a personal connection to that service because a few years earlier I did the neurology rotation of my internship there and had many positive memories. There was also a rumor that neurology would no longer be consulted on strokes but they would be done by a hospitalist who “had an interest in strokes.”  Both of those developments had a profound impact on morale. There were rumors of early retirement and looking for jobs elsewhere. We lost our geriatrician and then our social worker.  It was down to me, the neurologist, and our RN who gathered a significant amount of collateral history before the patients came to the clinic.  Word eventually came down that “we can no longer afford the RN.”  The neurologist and I looked at one another and decided that would be the end of the clinic.  We both had other jobs and did not have the time to spend additional hours rooming patients and collecting preclinic data.  We also knew we needed that data to do an adequate job. It is impossible to assess and treat people with significant cognitive problems without collateral information. About a year later, the neurologist left to head an Alzheimer’s Clinic at a major university medical center.  

Flash forward to today.  I am standing in front of a shiny new Neuroscience Center. For the past 9 months – I have had a new onset of headaches on top of rather chronic headaches that are related to cervical spine problems that probably date back to when I was a kid playing football. I set this appointment up myself after being assessed as having “tension headaches” and a “non-focal neuro exam.”  This post is not about the differential diagnosis of headaches (although it could be) – so I am not going to elaborate on the symptoms.  I will only say that I have street cred in neurology and had additional thoughts on the headache type and whether you should image the brain of an old man with a new onset significant headache.

Refocusing on the neuroscience center it is immense and obviously very expensive.  I go the neurology clinic on the 3rd floor and it is a large airy atrium with southern exposure glass.  It is so large that the entire medicine and medicine subspecialty clinics that contained our little memory disorder clinic could fit inside of it – it could possibly contain 2 or 3 of them.  The other striking feature was that there were hardly any people there. There were 4 demarcated pods with seating for about 24 people in front of each pod.  It was 2 o’clock and only two of us were sitting there.  I happened to be there only because I got on a cancellation list – my original appointment made in January was not until September.

The patient waiting area was impressive but as I was called to go into an exam room – I was not prepared to see the staff support on the other side of that door. There was a sea of cubicles stretching to the back of the building – many containing staff who all seemed very busy. As I sat in the exam room – I watched the big screen TV on the wall proclaim that this was the largest free standing neuroscience center in the Midwest.  I noticed that they did not specifically refer to physicians or medical doctors only “clinicians” despite naming every other profession on the team.

The examination itself was uneventful and “non-focal.” A couple of minor errors were made but nothing to mention here.  I am scheduled for brain imaging and a follow up appointment.

What was prominent on my mind?  What happened to my Geriatric Psychiatry and Memory Disorder Clinic?  The same management that decided one nurse was too expensive for my clinic sharing space with internists and minimizing neurology, was providing a raft of support in a $75 million state-of-the-art building for neurologists, neurosurgeons, PM&R and associated specialists.  Of course at that time there was considerable confusion and spin about the relative value unit (RVU) system of physician work units. Did work RVUs or total RVUs count? At one point they tried to tell us that only one psychiatrist in our large department was covering their salary. That went to RVUs needed to pay for rent and other staff.  It seemed like there was always plenty of Hollywood accounting.  It is another mystery of modern healthcare management and how middle managers increase exponentially in number.  There is probably something to be said for market concentration as well and how American governments tend to provide corporations with much more leverage than individuals or smaller businesses. 

At any rate it seems like they finally figured it out....

 

George Dawson, MD, DFAPA


Thursday, May 25, 2023

The Tomorrow River

 



The Tomorrow River is a small Wisconsin stream that crosses US Highway 10 three or four times between Fremont and Waupaca.  It eventually runs into a creek and becomes the Waupaca River.  I crossed all those tributaries twice on a trip last weekend. It gave me the usual opportunity to free associate to my past life. Two memories came immediately to mind – both from about 1977.  I was freshly out of the Peace Corps and trying to establish myself in a job as a research assistant cloning trees at an Institute in the area. That involved a lot of travel down Highway 51 to Highway 10 and I did not have a car.

One day I was travelling on a Greyhound bus heading to my apartment.  That was the first time I caught the Tomorrow River sign, as I looked up from a letter I was writing to my friend Glenn. I had a good experience in the Peace Corps entirely due to the Americans I met in my group.  They were bright, excitable, and energetic. We had gatherings where we listened to music, ate pizza, and played basketball.  We had long discussions into the night about what was important, what art meant, literature, music, math, science, and the meaning our work as high school teachers in the Peace Corps. We read the hipster literature of our time – Kerouac, Pirsig, Kesey, Brautigan, Wolfe, and others.  There were animated discussions and arguments.  All of that probably influenced the letter I was writing and then I saw the sign. The letter took on a surrealistic quality that Glenn appreciated in a letter he sent back to me.  As I visualized that decades old experience – it was a good feeling. I still feel a connection to my Peace Corps friends even though it has been decades and we rarely see one another or communicate.  I know that when I do – we will pick things up the way they have always been.

Between the second or third Tomorrow River sign there is an uphill curve in the road that bends to the left when you are traveling east. It is a long half mile bend. Later that same year just after Thanksgiving – I was getting a ride to my apartment from my friend Walt.  We went to the same high school and college. He was two years younger than me. Walt’s personality was completely the opposite of me. He was spontaneous, outgoing, and engaging. He could joke about anything.  I was the lab assistant in his organic chemistry section and one day his condenser hose broke loose and started spraying water just over the top of a freshly cut pile of sodium metal. I was able to grab the hose and redirect it.  Luckily there was no contact with the sodium, but after that point he started referring to himself and his lab partner as Captain Sodium.  On that day he was dropping me off and heading to his graduate program in endocrinology in Chicago.  The weather was not cooperating.  On that bend – the traffic that was usually travelling at 65-70 mph was at a dead stop in an ice storm and backed up for miles.  We both got out for a better view and realized it was impossible to stand on the road. Even  maintaining your balance, you eventually slid from the highest to the lowest part of the road and were forced to crawl back across the lane of oncoming traffic. We got back in the car and spent a long time joking about his bright reddish orange Dodge sports car and all of the trash talk he got from people in our home town about that car.  When he walked into a local bar he would hear: "Here comes the Fire Chief!"  We eventually completed the trip and I would see him from time to time over the next decades as he completed his PhD, then medical school, then residency in anesthesiology.  He became one of the top anesthesiologists in the country. And then several years ago, I got the news that he had died suddenly after a brief illness.  He was at the top of his game at the time – a department head and national expert in neurosurgical anesthesia.  I felt badly about not seeing him and not congratulating him on all of his success. I always feel badly when people don’t make it to retirement and a lot worse if I know them.  

Even before I went into the Peace Corps, I spent a lot of time navigating these roads with my friend Al.  We did that mostly in a 20-year-old Volkswagen beetle with a defective gasoline heater. When you tried to turn the heater on it might blow the hood open. Al was a mathematical genius and had accumulated almost enough math credits for a major when he was in high school - all self-taught by reading the texts. He decided to go to medical school and that led him to spend an additional 2 years as an undergrad taking the prerequisite courses.  Somewhere along the line driven by my insomnia and his sense of adventure, we ended up driving long distances to other towns at night to see movies or bands that we knew would never come farther north to our college town.  When you drive on roads in Wisconsin, Minnesota, and Michigan unusual things can happen.  When the pitch-black night is underlit by the snow cover – anything can happen. One night at about 2 AM we were on a road running parallel to Hwy 51 north when suddenly – an old model Chevrolet was airborne about 50 feet in front of us.  By airborne I mean it crashed over the top of a 5- or 6-foot snowbank at a high rate of speed and crossed our highway in a perpendicular path.   It landed on the other side of the road clipping the top of that snowbank first.  Turning around it was obvious that this was a planned attempt to launch the car from a parking lot outside of a bar to the other side of the road.  A few seconds later would have resulted in our Volkswagen being T-boned. That night we were able to turn up the radio and keep going.

These are the kinds of associations I have when I am driving these roads.  The paragraphs seem flat compared to the images in my head. I can envision my friends, images of what happened, the associated emotions, and the thoughts I have stacked on these events over the past 40-50 years. People I knew then often in a casual way.  People who I wanted to know better. People who – if I had interacted with them differently – would have drastically altered the course of my life.  People who I wish would call me or send me an email.  People who I regularly think about and dream about.  But then I tell myself – “This is your own weird perspective on life – most people don’t think like this.”  Generally, that is good to know but at the same time – people do reach out from the past. They seem to realize that we are not the same people we used to be – but the common experience means something.  In many cases, it means a lot.  At my 50th high school reunion, I was sitting outside of the main room when a classmate approached me and asked if she could sit down. I have known her for over 50 years and yet, that conversation was the longest I had ever spoken with her. It was longer than all of the conversations I ever had with her combined.  It was probably the best experience of the reunion.

I should probably clarify that I have no regrets and consider myself to be very fortunate.  All of these thoughts about the past don't cause regret - but there is often that feeling that you get when you go back to your home town for the first time. You see things in a different light.  You realize that you can't go back to the way things used to be. These thoughts have continuity with the present and the future.

At some point in the drive, I do a memory check.  I use the autobiographical memory test format and think of famous movie stars, visualize their image, and try to match names.  So far – so good.

I fantasize - primarily generative fantasies. I first encountered that term in the writings of the late Ethel Persons, MD.  She was an American psychoanalyst I found when I started to research fantasies in the 1990s.  She seemed to be one of the few psychiatrists writing about it. Generative fantasies are primarily problem solving fantasies that are more stimulating than coming up with lists in your head or your software. As I type that I am reminded of another road trip (east of Duluth on Hwy 2) when my wife asked me: "Do you ever have fantasies?' I told her I was fantasizing right at that time and she was very interested in the content. "I was thinking about what it would be like to win the men's 500M in the Olympics." She knew immediately that I was thinking about speedskating. I took up speedskating during residency and got quite good at it in my 40s. I was never an elite speedskater by any means, but I had the movements down, could endure the pain, and skated a lot of laps.  Part of learning the movement had to do with fantasies and thinking about the skaters I was seeing in the Olympics and racing against and remembering any advice I had received. I always have plenty of these thought patterns that seem focused on a hypothetical future.

 As a student of consciousness, I always wonder about how all of these thoughts are generated and (as a psychiatrist) what they might mean. Twenty years ago, I did a presentation on what I called the bus theory of the human brain. In computers, a bus is any system that connects components and allows data transfer between those components.  I decided that there was not enough emphasis on white matter and studied those tracts, their fiber content, and tried to calculate the bandwidth of those fiber tracts. At about the same time, I was wrapping up a course that I taught for many years on dementia diagnosis and cortical localization that was more of a behavioral neurology approach to the problem.  I tried to think of all of the recent papers I had pulled on hippocampal connectivity and recent papers on the neurochemistry of the hippocampus.  I thought about a paper I recently read on entropy and consciousness and whether thermodynamics could be a granular explanation for conscious states.  I am still a skeptic.

My wife wakes up.  We are driving home from her high school class reunion. There is a significant celebrity in her class and he sent a video when he could not make the reunion. The audio-visual equipment did not work, but we could see his projected image. We start to talk about the events of the night and what some of them might mean.  We talk about the A-V problems and the celebrity who clearly has become a projective test for everyone in her class. We talk about how good it will be to get back home and what we will need to do to reestablish the routine.

Thinking is a big part of life for me and life is very good…..

 

George Dawson, MD, DFAPA  

 

Photo credit for this one goes to my wife.  That is a Tomorrow River sign shot alongside Highway 10 last weekend.


References:

1:  Osanai H, Nair IR, Kitamura T. Dissecting cell-type-specific pathways in medial entorhinal cortical-hippocampal network for episodic memory. J Neurochem. 2023 May 30. doi: 10.1111/jnc.15850. Epub ahead of print. PMID: 37248771.


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.