Drug delivery technologies bring pharma and medtech into partnership. But does a perfect wedding always lead to happiness in the boardroom? Martin Goldman reveals the secrets of an unlikely couple.

The past ten years have seen a subtle slowdown in the development of new treatments for diseases. Pharmacological advances are not at the breakthrough level that was seen in the last part of the 20th century. Combined with that is the increasing difficulty of obtaining regulatory approval for new medicines, and the reluctance of the reimbursement authorities to pay increasing prices for medicines that are not perceived to offer extra value. Basically, it’s a cold world out there – and even a bright new molecule is treated with suspicion. If it’s that good, the thinking goes, there have got to be side-effects.

Let’s stick together

One smart solution to this difficulty has been to associate medicines with better delivery systems – a marriage between medicines and medical devices. Sometimes it’s a perfect match: an existing device is used for the delivery of a known therapeutic entity in order to improve patient outcomes. Sometimes the marriage can turn sour, and the fairytale romantic union can fall apart (see details below). As in life, some of the marriages are complex, and may involve additional partners. The good news is that divorce is rare (though not unknown) – and even then, a better partner may be around the corner.

At the end of the day, the use of medical devices in the delivery of medicines is driven by simple objectives:
• To enhance the safe, effective delivery of medicines and improve the human condition.
• To enhance or retain the profitability of a medicine and improve the mood of shareholders.

In an ideal world, these objectives are mutually assured; and in the current context of a relative famine in the pipelines of major pharma companies, it looks an attractive option. It seems a self-evident prediction that companies will turn to partnerships to enhance their own prospects.

In the October 2007 supplement to Scrip, Gorin and Tuttle reviewed drug delivery and its relationship to creating and capturing value for products. They contemplated a number of scenarios, which included putting old products into newer delivery systems, and the riskier situation of marrying together new drugs with novel delivery systems. Whatever the model applied, the truth is that the added delivery system (which typically adds to the product cost) must add true value to the whole system – usually by presenting a new technology that did not go with the medicine before, or adding some real therapeutic value that enhances the characteristics of the medicine for the patient.

The outcome of such partnerships should be products with such indisputable added benefit to the patients that the payment systems do not baulk at the added cost. Doing the same job with the same outcome in a different way is not good enough. My own simple approach is to ask: “Does the product bring as much to the practice of medicine as putting bronchodilators in metered dose inhalers achieved?”

The way we were

Through the retrospectoscope (with its 20:20 hindsight), we can look at Pfizer’s recent problems with Exubera. On paper, the project looked great. Injecting insulin is an obvious pain to the patients, and may even create compliance issues resulting in loss of control of diabetes. Surely a less invasive way of giving the drug is a no-brainer, especially as you cannot take insulin orally.

Exubera was described by Pfizer as a “major medical breakthrough in the treatment of type I diabetes”. However, once out of controlled studies, it displayed dosing and side-effect problems. The system added to the complexity of treatment – and the outcomes it produced appeared, at best, no better than those achieved by injection. It was a bitter blow for Pfizer when NICE decided not to endorse the product. Pfizer apparently walked away, leaving its partners in development holding the baby, and the contract device and component producers suddenly found the attractive partnership torn asunder.

The moral is a key principle for the devices industry: for any device that is part of a technology partnership, there must be true added value in the system. However, improving on current technologies is still worthwhile. For example, the HumaPen Luxura HD insulin pen for children is a potential winner if Lilly’s value claims of improved precision and ease of use in treating childhood diabetes pass the test of time. The system is potentially adding value to Lilly’s range of injectable insulins.

My own simple approach is to ask: “Does the product bring as much to the practice of medicine as putting bronchodilators in metered dose inhalers achieved?”

My heart will go on

Even the best relationships may not work out. Towards the end of 2007, it looked as though the marriage between coronary artery stents and anti-clotting medicines was at an end. Drug-eluting stents have been proven to reduce the occurrence of in-stent restenosis and the need for subsequent target vessel revascularisation compared with bare-metal stents. However, the safety of drug-eluting stents has been called into question because of an apparent increase in late stent thrombosis, a frequently fatal event.

An article published in JAMA (17th December 2007) assessed the evidence and appeared to suggest that the net clinical benefits of drug-eluting stents outweigh their risks. Jeremiah and Kirtane concluded that, according to the evidence, drug-eluting stents relieve obstructive coronary artery disease, provide durable mechanical results, and do more good than harm; but all patients should also be given antiplatelet and other optimal medical therapies to achieve the best outcomes. (An example of how a third party becoming involved can give the marriage more stability.)

This is certainly an improvement on the press releases that came out earlier in 2007, suggesting that the stent-producing companies would see their profits and workforces shrink. It seems to me that the story is far from over, and newer stent paradigms may supersede the current ones – a view supported by the news that the FDA has approved the Endeavor zotarolimuseluting coronary stent for use in treating patients with narrowed coronary arteries.

The air that I breathe

Recently, I have been involved in a project that brings together an old product – used as a nebulised antibiotic for the treatment of chronic lung infection in patients with cystic fibrosis – and newer technology. The art of nebulising antibiotics using electro-mechanical and, more recently, piezo-electric devices has emerged through pragmatic use rather than prospective hard science. Despite the inherent inefficiencies of jet nebuliser systems, enough of the drug can be delivered into the lungs of affected patients to produce a measurable effect, potentially prolonging their lives.

It seemed a self-evident idea to deliver the medication by dry powder inhalation, which is the de facto standard for respiratory medicines. However, during the development process a number of issues have become evident that relate to the drug-device combination:
• As we have to prove the efficacy, safety and quality of the pharmaceutical ingredient, it has also been necessary to prove the advantage of the delivery system given a similar clinical outcome. This can be measured as increased convenience for the patient, and measures such as quality of life and other patient-reported outcomes are becoming the standard way of quantifying the added value of delivery systems.
• Pharmacovigilance economic data will be a potential plus point, and may help to convince potential purchasers.
• It is clear that the use of a delivery system must provide some added value that is immediately evident to the patients. For example, while a dry powder inhaler system may be intuitively more attractive than a nebuliser, if multiple actuations are necessary to obtain the same treatment effect then it may be perceived negatively.
• If the device is for use with children, there should be documented evidence of this. Under new regulations that come into force in 2008, a paediatric investigation plan is needed that fits the intended patients. There should also be evidence that the product and device are specifically suitable for the children’s age range – they should not be treated as small adults.
• Keep it simple. Devices should not add complications to the delivery of medicines, but remove them. Disposable devices do away with the need for complex cleaning and concerns about contamination and crossinfection. Cost clearly needs to be thought of as part of the ‘added value’ equation.
• If the system is for multinational use, it is good practice to check the acceptability of the device to varying markets and the applicability of patient-reported outcome measures. The language used will need to be adapted to each environment.

Tougher than the rest

  There seems little doubt that judicious use of devices can add value to medicines and enhance their attractiveness to prescribers and users. A recent example of this is Janssen-Cilag’s Ionsys delivery system for postoperative pain control, a needle-free and patient-controlled iontophoresis system to deliver fentanyl. This immediately addresses the major shortcoming of previous PCA systems. The manufacturers will need to provide data about patient pain relief, but otherwise it seems to tick all the boxes for a well-planned device application.

One of the major concerns of pharma companies at the moment is the fragility of the patent system. Given the long time it takes to bring a new molecule to market, loss of patent life is loss of money. The incorporation of a device enhances patent protection, and may even restore protection for older products. While a competitor could produce alternative devices, typically this takes a lot of time and money. If devices are computercontrolled, the software can be copyrighted as well. Much interest is being shown in orphan drugs at the moment, and delivery systems would float these drugs on a raft of protections including market exclusivity and addition benefits for a paediatric indication (two years’ additional market protection). This paints a complexly attractive picture wherein manufacturers can protect their investment.

Where we belong

Medical devices have provided extra value for medicines, and can do so in the future. Devices have the potential to enhance patient care, clinical outcomes and quality of life. The main problems are the complexity of the systems and the need to prove true added value. It is not enough to be as good as an existing product: the addition of a device should provide clear advantages that are consistently measurable. Just adding go-faster stripes will not work. Device-drug combinations need to be shown to have an acceptable benefit/risk profile, and each new product should have a risk management plan.

Given the ethos of social medicine systems to opt for the cheapest product, it becomes essential to prove that the outcomes of premium price products have clear added value in terms of healthcare outcomes with no added complexity. The good news is that the device industry is probably more adaptable than its pharmaceutical counterpart, offering strong positive prospects for patients, doctors and shareholders.

Dr Martin Goldman qualified in Medicine and practised initially in hospitals. He has worked in the pharmaceutical industry for over 25 years, and has been involved in a wide variety of medical department activities – including, most recently, the development of a novel dry powder inhalation system for delivery of antibiotics to the lungs.