Introduction
The last few years have not been easy for the pharmaceutical industry. There has been a slowdown in sales in developed countries, pressure on drug prices; mega mergers and lay-offs. Quite a few marketed or promising pipeline drugs were either scrutinized by regulatory bodies or may not even make it to market. This decade many mega blockbusters will lose their patent protection; many blogs suggest that existing pipelines will not be able to replace anticipated revenue losses.
It is a safe bet to assume that pharmaceutical companies will use all available tools and resources to protect their franchises and to minimize market share erosion once patents have expired. There is very limited experience available in the biotech world, but it is expected that the arrival of biosimilars will have a negative impact on the originator products’ sales.
Versions of originator biologics that feature some molecular or chemical modifications like less frequent dosing, less toxicity or more potency may appear in the industry. At present, regulatory legislation does not provide a clear regulatory pathway for those ‘enhanced’ biosimilars. It appears that regular copycat biosimilars will hit the market first. One major play to differentiate originator and copycat products will be how the drugs will be delivered.
Consequently drug delivery will be playing an ever important role in those competition intensifying marketplaces. Virtually all biologics are given via the invasive route. Delivery systems that score high with users may provide a competitive edge as pharmaceutical companies start sharpening their life cycle management tools.
This article will review some of the latest industry news and events. It will try to put them into perspective and discuss some of the observations and trends we may see in the years to come.
Industry News
Insulin Delivery
All of the ‘Big 3’ Insulin manufacturers lately introduced enhanced versions of their injection pen devices. This fact on its own demonstrates the importance those manufactures place on delivering the drug with the right tools.
There are reusable and disposable (pre-filled) injection pens on the market. The launched enhancements are typically not disruptive but still warrant to often remove the older versions of those pens from the market. The new features include digital dose memory and recording; new dosing mechanism and a user friendly design interface that makes for i.e. easier dose dialing or lower force to deliver the drug.
Interestingly, the devices can be customized for market segments like the pediatric market with child friendly features like bright colors, lively images or special covers.
In the area of Insulin pumps that get attached to the patient’s body for up to 3 days, a new disposable device is now used regularly by over 20,000 American users. This customer base is rapidly growing.
For severe Hyperglycemia treatment, one of the Insulin players is partnering with a third party to develop a single use auto-injector ‘pen’ device which may considered to be an important advancement for patients. This is in line with the trend for further user convenience in diabetes care.
Pen needle manufacturers also launched innovations. A thinner and shorter 32 G 4 mm pen needle is now available. Also most pen manufacturers are now offering safety pen needles featuring automatic accidental needle stick prevention.
Needle Free Delivery
At the beginning of 2010, the first disposable needle free device was launched (Figure # 1). It was filled with a generic anti-migraine drug. As needle free technology had limited success in the past this event and its success will be monitored by the medical community with a lot of interest.
Around the same time a reusable needle free device was launched by a major generic company for human growth hormone. Here as well it will become interesting to see how this technology will do in a market historically dominated by needle based devices that improved over time.
Accidental Needle Stick Prevention
Driven by legislation and the desire to stay competitive many more drugs became available with automatic needle guards. Those were mounted on pre-filled syringes with staked needles (Figure # 2). Historically, pre-filled syringes for anti-coagulation drugs were converted to automatic needle guards first, but now those are also available for pre-filled syringes for autoimmune diseases treatment, G-CSFs, ESAs and other drugs.
The market for pre-filled syringes and accidental needle stick prevention is growing rapidly. Another manufacturer is developing a pre-filled syringe with passive safety features that are fully integrated in the glass barrel. This eliminates the attachment of ancillary safety products like needle guards onto regular pre-filled syringes. Upon the delivery of a full dose, a passive retraction mechanism is activated, whereupon users may control the speed of needle retraction directly from the body into the barrel of the syringe to virtually eliminate the risk of needle stick injury or blood spatter.
Lastly, it can be reported that one of the major suppliers of automatic needle guards for pre-filled syringes was acquired by a multinational corporation. This suggests that the technology has become an important asset for companies that desire to offer multiple delivery solutions in the field of injectable drug delivery.
Auto-injectors
Lately we could witness more device launches for autoimmune drugs. One disposable auto-injector was launched in the EU in 2009. A similar auto-injector was already available for the same franchise in the U.S. since 2006. Again, it will be interesting to watch what this device launch will do for the competitiveness of the drug.
In the same therapeutic area, there was another introduction of a new drug with a disposable auto-injector and a customized pre-filled syringe that should provide support for self-injecting patients, some of them with severe dexterity issues. All in all 3 device launches in the same therapeutic area were to be reported within a short period.
‘Smart’ Injection Devices
The first electromechanical injection device was launched for human growth hormone a few years ago. A similar hybrid version was launched in summer of 2009 by the same pharmaceutical company for self-injecting multiple sclerosis patients in the EU and in Canada. Like its predecessor this electronic motor driven device features an electronic skin sensor and patient comfort settings. Some of those are adjustable injection and needle insertion speeds; dose memory and log; and an LCD display that guides the patient through all steps of the injection. All kinds of injection data are recorded and can be reviewed if needed.
In the epinephrine field, a large pharmaceutical company signed a license deal with a device company for a novel epinephrine auto-injector. Until now this market is dominated by pen-sized auto-injectors. Those were not always intuitive for an untrained user. The new device has the goal to be more intuitive and compact than the existing solutions.
The result is a credit card sized device that ‘talks’ the user through the epinephrine injection process. This may be a big advantage as the injection might have to be given by a parent or a baby-sitter who may have never used an auto-injector before.
Changes of Delivery Routes
Another deal in the injectable drug delivery space took place last year. A multinational pharmaceutical/biotech firm signed an agreement with a drug delivery company. The multinational will invest to manufacture a device that enables subcutaneous delivery for some of its large injection volume biologics.
A standard bolus subcutaneous injection typically is limited to around 1 ml without causing injection site irritations or leaking back out. This technology under development allows injecting larger volumes by opening up a cavity in subcutaneous tissue for a short period of time. It has the potential to convert previously intravenously delivered drugs to be given by the subcutaneous route.
The device will be attached to the injection site by a health care professional or the patient himself; the needle is inserted; the device injects the drug over time; this is followed by automatic needle retraction (Figure # 3). In the oncology field, the opportunity may be bigger outside the U.S. where physicians generate income from giving I.V. infusions.
Switching from intramuscular or subcutaneous to intradermal injections is another new field of interest. Drugs get injected shallowly into the dermal layer of the skin that contains a dense network of lymphatic vessels feeding local lymph nodes, resulting in rapid therapeutic response. The needle or needles are around 1.5 mm in length which is considerably shorter than the standard needles.
Discussion of some market events
Most of the before mentioned industry news and events need to be seen in the light of intensifying competitive activities. The market is changing and drug delivery will play a major role in this. Here is a discussion of some events:
An easy to use; few steps-to-operate needle free device has been commercialized. Does that mean there will be more launches of this kind in the near future? And what kind of ‘evidence’ does the market need to see in order to make this happen? Clearly, the concept of no needle looks appealing to many, but how will the device perform in terms of user acceptance and how will the perceived injection pain picture look like? Post launch surveillance will generate data that will provide some insights.
• The launch of electromechanical devices so far is yielding success. The first device in the human growth area propelled this franchise from 5/6th place to 3rd place worldwide. The hybrid version launched for the MS drug is so far way above its own forecast. The future will show whether this device concept is successful in markets with frequent injections like daily or three times weekly respectively or beyond that.
• The Big Pharma deal for the epinephrine device suggests that big Pharma firms start looking at niche markets. This view can also be supported by a recent bid of the same company for a niche Biotech outfit. It will be exciting to see how users will react to the new epinephrine delivery device with integrated electronics that guide users through the injection process.
• The pre-filled syringe with an integrated passive automatic safety feature will most likely be introduced into markets where attached automatic needle guards reign so far. The new technology would bring along potential advantages like less assembly in pharmaceutical manufacturing and would come with smaller secondary packaging requirements. User preferences need to be tested and will show whether the technology has the potential to be disruptive in its class. If this were to be the case the technology could become a genuine brand differentiator.
• One major vaccine company filed a supplemental Biologics License Application (sBLA) with the FDA for their flu vaccine. They are hopeful that providing a less invasive option may be preferred by patients. This kind of vaccination is believed to stimulate a desirable antibody response. It needs to be seen whether the technology is applicable for other injectable drugs outside immunization. The short needle may have the potential to get patients vaccinated against flu that previously opted out of it.
Observations and Trends
‘Mandatory’ Device Launches
In certain markets – especially those in which devices are rampant – it is becoming highly recommended to launch a drug with a device. This statement gets supported by three different devices launched in the same competitive autoimmune market. Two of the devices were disposable auto-injectors and one was a customized pre-filled syringe.
Furthermore, a major generic manufacturer announced that they will partner with another company to develop a pen injector to deliver Follicle Stimulating Hormone (FSH). This is historically a market for self-injectors and already dominated by injection pen devices. Consequently every new entrant into this market needs to have a competitive device if they want to be successful.
The above evolving situation is already a standard for treatments with Insulin or human growth hormone. For years market players battle it out with drug delivery devices being the major differentiator. These insights on the significance of devices start now to apply for other therapeutic classes as well.
Disruptive Technologies are Add-ons
When electromechanical devices were launched for human growth hormone and multiple sclerosis treatment, they did not replace the already existing device platforms for the respective franchises. Those were injection pens, reusable auto-injectors or reusable needle free devices.
No forced conversion was to be seen in either market. This strongly suggests that different delivery technology seem to have different appeal to various self-injecting patient segments. In highly competitive markets, it is worth to provide multiple product platforms to address different needs.
Enhanced Devices Replace Previous Ones
In highly competitive markets, like Insulin delivery injection pens remain the dominant delivery method. It became a pattern that on a regular basis existing pens got replaced through newer and enhanced generations of injection pens.
All big players have slick new pen designs with enhanced features. Interestingly, companies seem to place more resources than before into revamping design. This applies for functionality and for aesthetics alike. Specialized design companies may provide further input for drug delivery moving forward. There seems to be added value focusing on the patient experience. Enhanced focus will be on all aspects of design and especially on user perceptions – leaning on the consumer products industry vast experiences in that field.
More discretion for daily injections is another need to be addressed. Pulmonary Insulin delivery may so far have failed as one launched enabling device looked more like a small fire extinguisher. New devices may help to reinforce positive feelings - They could even be presented in a non-medical set-up like a cosmetics case or similar.
Subcutaneous Injection Preferred
The previously mentioned arrangement describing the potential switch from I.V. to subcutaneous drug delivery confirms the potential attraction of the latter delivery route. Some industry players see a genuine transition as investment is moving towards subcutaneous auto-injection development away from other competing technologies like pulmonary delivery.
So called micro infusers deliver subcutaneously doses higher than 1 ml. The technology infuses those higher doses – also higher viscosity drugs can be accommodated – over time. The device is attached to the skin with the help of an adhesive. The needle is inserted automatically followed by automatic dose delivery. This process may take several minutes or hours. When the injection is finished the device is removed from the injection site and the needle is safely locked away to prevent accidental needle stick injuries.
The combination of automated subcutaneous delivery whether it is with an auto-injector, injection pen, micro infuser or needle free device holds promise especially for larger molecules. It allows delivering a dose safely and complete; the technology can be used for self-administrating patients; and has potentially a clearer regulatory pathway than some technologies that are in their early stages like pulmonary, nasal, or intradermal.
It needs to be seen whether we will witness many switches from I.V. delivered drugs to subcutaneous delivery. Apart from feasibility the outcome will also be a function of payers’ and health care providers’ responses.
Concluding Remarks
Increasing competition will continue to be the big driver for future innovation in the drug delivery space. Delivery of a drug is already the main differentiator in some therapeutic classes and will be more so in the years to come.
Also, in therapeutic classes where devices play already a major role, it seems almost mandatory for new entrants to have at least one device presentation when launching a drug into that space.
New drivers of change are emerging in invasive drug delivery. Many large molecule pipeline drugs have higher concentrations, volumes and viscosity. Many of those products are for chronic therapies and have the potential for self-administration. New devices, but also new primary container technologies need to support this. The latter could be cartridges or plastic pouches to accommodate higher drug volumes. Material wise glass used to be the gold standard, but lately plastics like cyclic olefin polymers have been identified as potential alternatives to glass and also been commercialized in smaller numbers.
With drugs being increasingly self-administered factors like design, functionality but also aesthetics will play an important role. Lessons learned from consumer marketers will be incorporated into drug delivery development from early stages onwards. Drug developers need to learn to work not only with health care professionals, but also with patients to better understand their user and psychological needs.
The role of electronics will be further defined. While simplicity may be important for certain patient groups, others may embrace technologies that allow them to be alerted, log information and guide them through the injection process.
Moving forward payers may become more interested what drug delivery and devices can do for patient adherence and outcomes. Are there potentials for genuine savings if compliance improves? Can health care professionals better monitor the success of their prescribed therapies? Apart from product differentiators devices and drug delivery may be able to contribute in realizing savings for the health care systems.
This could be the next driver in the innovation cycle.
References
1. Mark Ratner; Nature Biotechnology Volume 28, Number 4, April 2010; p. 298
2. Andrew Jack; A pharmaceutical experiment in design, Financial Times, 8/26/2010
3. Ian Mawhinney; A new delivery landscape; Drug Discovery & Development; 12/07/2009
4. Alan Morris, Andreas Knaack: Advanced delivery devices; in: Dry Delivery Technology, March 2010, Vol 10, No 2
5. Matthew Young: The next generation of auto-injectors; in: OnDrugDelivery; July 2010
Author Biography
Mathias Romacker has been Principal Business Analyst at Amgen Inc. in Thousand Oaks, Calif. since January 2006. In this role he is involved in tracking and evaluating technologies for injection devices and primary packaging for the invasive delivery of Amgen’s launched and pipeline drugs.