Dazed and confused

With no regulations in sight, low returns and stale product pipelines, is the anaesthetic drug market facing a dead end? Aashruti Kak finds out if there is any glimmer left in the fire

Prior to anaesthesia, surgery was considered as a terrifying last resort. Some doctors tried alcohol, morphine and other sedatives to kill the pain of surgery, but mostly, patients were held or strapped down, some luckily fainted from the agony, but many died. Anaesthesia gave surgeons more time to be more accurate and perform more complex procedures. Judging by this we can say that we sure have been lucky to have come a long way.

Today, surgeons have a decent list of reliable anaesthetic drugs to choose from, depending on their classification.

Anaesthetic drugs are classified based on the basis of application (local, regional, general and neuromuscular blocking agents) and mode of administration (topical, injectable and inhalable). It is the above categories which decide what penetrates the market. According to a Datamonitor Market brief: Competitive positioning in the anesthesia market in April 2000, the balanced anaesthetic approach, in which different drugs are used to reach specific desired endpoints, is currently the most common method of providing general anaesthesia. Injectable forms are most commonly used anaesthetic drugs because of their ability to cause local or regional anaesthesia. Inhalable drugs are mostly drugs that result in general anaesthesia. Topical drugs are primarily used for temporary pain relief or numbing of a small area, particularly for interventions like the surgical removal of devitalised tissue by a physician.

A sleeping view

"Since the anaesthetic drug market witnessed the launch of its last NME in 1999, there is every possibility that there will be a gap of nearly 20 years or more before the next NME reaches the market" - G Venkateswara Rao Senior Consultant-Healthcare Consulting Datamonitor, India

G Venkateswara Rao, Senior Consultant-Healthcare Consulting, Datamonitor, India, says that the global anaesthesia market in 2007 was valued at $4 billion and injectable anaesthetic drugs accounted for more than 50 percent of the market, while inhalable anaesthetic drugs accounted for about 30 percent. Sevoflurane, and propofol are the two leading off-patent drugs in the anaesthetics market with sales of $925 million and $805 million, respectively in 2006. Together, these drugs account for about 43 percent of the total anaesthetic market. The originator brands of these drugs, Ultane (sevoflurane) from Abbott Laboratories and Diprivan (propofol) from AstraZeneca still command the highest sales in their segments, with sales of $799 million and more than $500 million, respectively in 2007.

"The global anaesthesia market is highly competitive because it is essentially a generic market with no new drugs launched since 1999 (when dexmedetomidine was introduced)," says Rao. According to the Datamonitor Market brief, although the anaesthesia market is a genericised market, there are relatively few players in each of the segments. "This is because the entry barriers are high, particularly in the inhalable anaesthetics market, with the need for specialised distribution network and production facilities, and the existence of process patents for some of the leading products like sevoflurane," he adds.

With sales in excess of $800 million in 2007, AstraZeneca and Abbott are the two leading companies in this market, accounting for about 40-45 percent of the total global anaesthetics market. The third leading player in this market is Baxter Healthcare with the total sales of $422 million in 2007. Other players include Claris Life Sciences, Hospira/Mayne, Abraxis Pharmaceutical Products, Piramal Healthcare, etc. Claris has Provive/Profol, which is an internationally accepted brand. It is also the only company to offer Sufentil (sufentanil) in India, which is a narcotic analgesic. Other anaesthetic products include Sedoz (midazolam), Ketajex (ketamine), Thiojex (thiopentone), Sensinil (lidocaine) and Bupican (bupivacaine). Piramal Healthcare manufactures, distributes and markets halothane and isoflurane (both are inhalational anaesthetics) in India and UK and exports to 90 other countries.

Over the years, as some of the research-based pharmaceutical companies like GlaxoSmithKline, Wyeth, Eli Lilly, AstraZeneca (only the US portfolio) have disposed-off of their anaesthetic drug portfolio, the dominance of specialty generic companies has increased in this market, and so have the entry barriers.

The size of inhalable drugs market was about $1,160 million in 2006 because of highly generic nature of this segment, says Rao. According to Datamonitor, the size of the market is estimated to have remained the same in 2007 as well. "Sevoflurane accounts for about 80 percent of the inhalable market, followed by desflurane (12 percent), isoflurane (approximately seven percent) and enflurane (approximately one percent). Abbott, the originator company of sevoflurane, dominates this market with Ultane, accounting for about 69 percent of this segment," he adds. Companies like Abbott, Baxter and Minrad have process patents for sevoflurane and are raking-in high margins due to their virtual monopoly for this product. The other leading companies in this segment are Baxter, Minrad, Hospira, Piramal Healthcare and Halocarbon.

In pharma's cookbook…

Currently, Rao says, there are about 35 drug candidates for anaesthesia in various phases of development across the world. Most of these drug candidates are re-formulations of existing drugs. "There are only two drugs (both re-formulations) that are planned to be launched in the market during the next six months. They are Akorn's undisclosed gel formulation for use as ocular anaesthetic in opthalmic surgeries and a water-soluble prodrug of propofol licensed from ProQuest Pharmaceuticals by MGI Pharma, as a potential injectable anaesthetic agent. These two drugs received positive opinion from US FDA for their New Drug Applications in June and May of 2008, respectively," reveals Rao. Interestingly, other than the re-formulations, there are no (entirely new) new molecular entity's (NMEs) in the development pipeline, and so, it is likely that there may not be any new anaesthetic drug launches in the next eight to 10 years.

"Since the anaesthetic drug market witnessed the launch of its last NME in 1999, there is every possibility that there will be a gap of nearly 20 years or more before the next NME reaches the market," he says.

According to the Datamonitor Market brief, there are a number of unmet needs associated with the existing classes of anaesthetic drugs in terms of their side-effects like nausea, vomiting, persistent narcosis, post-operative pain, etc. Anaesthesiologists often prefer working with drugs with well established safety, fast onset of action, quick recovery, and also drugs that lend themselves to the practice of rapidly changing the depth of anaesthesia or muscle relaxation according to fluctuating surgical stimuli (eg cardiovascular stability).

"However, a recent study conducted in UK found that the industry perceives that there is little need for new drugs in anaesthesia because the needs are well addressed by existing agents. Even so, there is clear evidence to back the assumption that unmet needs exist, because drugs like Penthrane (methoxyflurane) and Raplon (rapacuronium bromide) from Organon have been withdrawn from the market due to their side-effect profiles," says Rao. Raplon, an intravenous drug, was withdrawn in March 2001 from the market (after a period of about 18-19 months) as it had resulted in the death of five patients who received it.

Contrary to the findings above, there is an experimental drug that has shown groundbreaking results and has been termed 'revolutionary' by many anaesthesiologists world over. Sugammadex, a novel selective reversal binding agent (SRBA) under development by Schering-Plough (which it acquired through its combination with Organon BioSciences in November 2007) is currently under review for marketing approval in the US, Europe and Japan. If approved, sugammadex will be known by the trade name Bridion and will be the first and only reversal agent of a new class, offering anesthesiologists the ability to reverse both shallow as well as profound muscle relaxation induced by the commonly used muscle relaxants, rocuronium or vecuronium, within minutes. Hence, it is expected to be far more expensive than the muscle relaxants present in the market.

In a recent development, some scientists from the University of California had found that sevoflurane gas, when given in low dosage, could block human emotive memory. If this could be further researched, it can provide clues to 'intraoperative awareness'—instances in which patients can recall the experience of undergoing surgery in case of anaesthetic drug failure in disrupting memory—and can help in patients erasing painful memories of their surgery.

Concerns and inclinations

Apart from the fact that development pipelines are cluttered with new formulations of existing drugs on the market, there are other issues that need notice. For instance, anaesthesia practice in India is extremely guideline deficient. According to Dr R P Gehdoo, Professor, Department of Anaesthesiology, Tata Memorial Hospital, currently, there are no guidelines laid down by the Indian Government for anaesthesia practice in India, and most of the anaesthesiologists in India follow the guidelines laid down by American Society of Anaesthesiologists (ASA). Similarly, there are no clear regulations specifically for the R&D of anaesthetic drugs in India.

In addition to the above, increasing use of endoscopy/laparascopy based minimally invasive procedures like arthroscopy and other gynaecological procedures as an alternative to open surgeries are also driving the need for anaesthetic drugs with faster onset and short duration by limiting the uptake of general anaesthesia drugs, says Rao. However, this trend is creating a demand for anaesthetic drugs that have a fast onset and short duration of action with minimal side-effects. He adds, "Advancement in medical treatment of diseases may limit the need for surgical procedures, and thus, the need for anaesthetic drugs. However, with the increasing ageing population and advanced surgical interventions for many diseases, the demand for anaesthesia drugs may see an upswing."

A major concern that ties all the processes together is the occupational risk that anaesthetic drugs put healthcare professionals into, in terms of unwanted side effects of anaesthetic drugs that occur during anaesthesia or during the post-operative recovery period on the patient as well as on those who are incidentally exposed to anaesthetic gases. After meeting regulatory requirements for marketing drugs, the qualitative and quantitative nature of side-effects of the drugs in the target population and the risk of incidental exposure of healthcare professionals are generally well defined. However, sometimes unwanted side-effects are first detected after post-approval marketing. Toxicity of anaesthetic drugs is one of the contemporary concerns with respect to side effects including delayed recovery of cognitive function, addiction and tolerance, local anaesthetic cardiotoxicity and tissue toxicity, relative toxicity of enantiomeric forms of drugs, and the role of biotransformation in unwanted responses to anaesthetic drug administration. There needs to be a thorough scientific inquiry that spans a range of disciplines from molecular biology to global ecology providing information that is essential for predicting, assessing, avoiding and treating the untoward effects of anaesthetics.

Future gazing

According to Rao, the anaesthetic drug market is likely to remain static in the next few years as the market is highly genericised with increasing presence of specialty generic companies and decreasing focus by research based pharma companies. This specialty market is likely to witness heavy competition with decreasing margins with the entry of new players. "Most of these specialty players are trying to create a competitive advantage by enhancing the performance of established drugs with new drug delivery mechanisms or devices.

Most of the drugs in the development pipeline are focused on either analgesics or neuromuscular blocking agents and not specific to the core application of anaesthesia. This is quite evident in the existing gap in discovery research aimed at a purely anaesthetic drug in the pipeline (other than the neuromuscular blocking agent—sugammedex). Moreover, the expected return on investments in new anaesthetics is low compared with other more lucrative areas such as oncology; and the cost of failure of these drugs is extremely high," says Rao. Having said that, ultimately, one has to remember that progress in anaesthetic R&D is bound to be slow, for it is much easier to estimate the potential of a cardiovascular or a diabetes drug than that of a new anaesthetic.

aashruti.kak@expressindia.com