Simplicity Wins with Combo Products: An Interview with Jim Collins

He spoke with the PDA Letter regarding the complexities of combination products. The following is the complete interview.

A Brief History of Combination Products

PDA Letter: What is the history of combination products and the concept behind them?

Jim: If you think about products that the FDA regulates—you have drugs, and you have devices—and somewhat historically, what ended up happening in the 1980s is that there was a realization that we needed to do a better job of using device technology to help people take their medicine. Injecting yourself or sticking yourself with a sharp object is not a natural act. The people who thought that was a good idea had self-selected themselves from the gene pool years ago. We are left with those who think we should not stick ourselves with a sharp object.

Back in the 1980s, a company called Nordis, which later combined with a company called Novo, recognized that people taking insulin three times a day had to carry around vials and syringes with them. So, when they went out to eat, they would have to go into the restroom with a vile and syringe and give themselves an injection. And as you know, when people see a vial and syringe, the first thing that they do not think is, ‘Oh, that’s an insulin user taking medicine.’ So, people in the company decided that if they could come up with an easier way to carry and administer the product at mealtimes, it could help them. This meant they could differentiate their products, and more people would buy their insulin. All of this kind of started in the 1980s.

The Four Megatrends

PDA Letter: In what ways have combination products evolved from the 1980s to today?

Jim: There are a couple of things to understand how these technologies evolve. The first is that the technologies really follow the molecule development. As new molecules come forward, delivery technologies are developed to help deliver those molecules. For example, injection pens, which are mostly used with insulin and daily administration of peptides, came before autoinjectors, and this was because insulin came before the development of monoclonal antibodies. If monoclonal antibodies came first, the autoinjectors would probably have come before the pens. This is why I try to tell people that if you try to figure out where delivery technologies will go, you want to ask yourself, ‘What are the innovative molecules that are coming?’

Also, certain megatrends have been important, and I think they will continue to be important, and I have identified four of them. However, they are not all equal. One of the most important ones is simplicity. This always wins in this area because healthcare professionals do not have much time.

For example, if you go and talk to your doctor, you are lucky to see the doctor for a few minutes before the doctor goes on to see the next patient. So, whenever you are taking your medicine, it has to be simple because people do not want to spend a lot of time taking an injection; people do not wake up wanting to do that. They might want to lose weight or get rid of pain, but what they really want is something that is a small thing that is a part of their life. From 1980 to 2010, maybe even through 2020, the major driver of all these technologies was to make them simple, with fewer steps, more accuracy, and easier to use.

The other three megatrends are cost, environmental concerns, and connectivity.

PDA Letter: Could you elaborate on what you are referring to regarding connectivity?

Jim: Connectivity, in this sense, is the ability of the delivery technology to capture data of when and how the product is being administered and also to provide information back to the user, healthcare professional, or the payer, which helps the patient use his or her product better.

For most medications, compliance is really low; there is a massive problem with compliance. Sometimes, people forget, and sometimes, they might not see results and ask themselves, ‘Does it really matter?’

However, I would make the case that the more a patient actually sees the results of their medication, the more compliant they are likely to be. For example, when people who have rheumatoid arthritis take their injection and are able to move better and feel less pain, they are going to be very well motivated for compliance. However, they might have an issue with the cost of the medication. Most of the time, in the United States, we pay three or four times more for medication than any other country. So, a good majority of the time, most people might not even be compliant as much as they would like because of standard things like copays, which burden most people.

With that being said, I think the opportunity with technology and data, if applied correctly, will help patients be more compliant. They could get a better idea about why their medication is important.

Now, that is what I mean regarding connectivity: digital integration. If you had asked me 10 years ago, I would have told you with absolute certainty that this was the future. I say that because I have known for a long time that if I could give people better information and data, I could likely improve the health outcome of the medicine. However, there is another challenge that has to be overcome, which is environmentalism. This is why I say simplicity undoubtedly wins.

[Editor’s Note: See the On The Issue video on the 2023 PDA Drug Delivery Innovation Award, which was awarded to Merck KGaA Darmstadt Germany for for their digital platform for enhanced adherence tracking for a growth hormone deficiency injectable treatment.]

Simplicity is Undefeated

PDA Letter: Would making combination products more cost-efficient assist in the simplicity or is the idea a bit more complex?

Jim: The answer is no because cost savings never get passed on to the consumer. For some monoclonal products and new innovative medicines, if you get the efficiency, the device can be a pretty significant part. However, the problem you typically see now is that the pharmaceutical companies are charging margins of 90-95 percent. The reason for this is because if a pharmaceutical company does not invent new molecules, they would potentially go out of business in 15-20 years. In addition, new medicines really do provide significantly high risk. So, the fact of the matter is, the basic business model of pharmaceutical companies is to make money on new medicines, and to reinvest that money into research and development (R&D); they could be reinvesting up to 20 percent in R&D.

Now, the other issue is when these companies make all of this money, the people who invest in pharmaceutical stocks expect a high profit margin.

PDA Letter: What clinical trials do combination products usually have to go through before being accessible to consumers?

Jim: The first thing to be aware of is that not all combination products are treated equally. The FDA prefers that your final combination product be used in your phase three clinical trial. So, when the FDA sees the data and effectiveness of the product, they would be able to judge the entire product of a device and drug when used together—this would be the FDA’s preference. Regarding asthma inhalers or inhalation devices, the FDA has been fairly strict on that goal. This is because they found that if people made changes to the combination product or the device part, it could impact the efficacy of the drug.

As you can imagine, with some of these pen devices, however, you can make changes that have no impact on the drug. So, the FDA has somewhat mentioned that unless you have an impact on a drug flow path, you can make some changes in the device as long as you can prove those changes do not impact the safety and efficacy of what you used in phase three. Now, there is another important tool that is specific to combination products, which is called human factor studies. Human factor studies are simulated use of the device with different user groups to test potential user errors that potentially exist and create a problem.

PDA Letter: Are there any new and innovative combination products that are being developed currently?

Jim: Typically, the device technologies being applied are pretty well-established. What is likely to change in the future are molecules and some emerging technologies.

Pertaining to small molecules, the combination products that are used there have two types of technologies: inhalation devices and passive patches, which were significant in pain treatment a number of years ago. Those are the technologies for small molecules that are applied. Now, when you look at biologics and peptides, there are usually three current technologies: pen cartridge systems, auto-injectors, and prefilled syringes. The one emerging technology I see coming is large volume injectors, patch injectors that deliver over 5 milliliters (mL) of product, possibly up to 25 mL.

Keep in mind that there are a lot of other technologies that I did not mention, and this is because I do not see them solving the core issues of simplicity, cost, connectivity, and environmentalism.

PDA Letter: How do you see the designs and/or material choices in the future being impacted with the need to move to be more green sustainable systems?

There are already over a billion disposable insulin pens that are being manufactured, sold, and thrown away every year, and we are probably not that far away from the same thing happening to autoinjectors. Someone might ask, ‘Well, is there a new technology that could help there?’ And I believe that, yes, there is. For instance, 1 reusable insulin pen can replace over 200 disposable insulin pens, and this technology has always been available. This goes back to my key point that simplicity undoubtedly wins. Patients might want to be environmentally friendly, which is a good thing, but they really want the easiest solution to treat their disease, which I mentioned before.

Also, reusable pens are better devices and cost less money. The problem is that a great majority of pharmaceutical companies do not align with this idea.

PDA Letter: Given that you have been involved in a lot of innovation in this space, what are a few of the most overlooked or underestimated critical path items that need to be fully considered when developing combination products?

The first and the most important is developing combination products that people do not want or need. Engineers often formulate an interesting technology and want to develop it, but that super cool technology does not solve a problem. Most companies do not understand the customer’s needs first. We have to realize that great product design starts with understanding the problem before you understand the technology.

The second is that it is not just about the device itself; it is about the system, and the system is made up of three elements: drug, container for the drug (like a type of syringe), and device. There will be major issues if you do not think about those three elements together. So, we have to understand the customer’s needs and then design the system. Companies need to start thinking about their delivery technology early in the process.

Conclusion

“The key to understanding the future, is to know what is driving the present,” Collins said after he ascertained that the future of combination products is in a good place. Collins conversation with the PDA Letter is an example of PDA’s mission, which is “creating awareness and understanding of important issues facing the pharmaceutical and biopharmaceutical community, delivering high-quality, relevant education to the industry…so members can better serve patients.”

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