Creating and manufacturing complex generics involves higher levels of expertise, planning, development and cost than standard generics.

“Getting the supporting data to show that your generic products are comparable to the brand originator takes time and calls for high investment in R&D,” says Jonathan Rousell, VP Generics RA Europe.

“And if for example you're looking at making polymers or peptides or liposomes, it takes a certain R&D skillset to develop these products - not every company has the capability or resources to create these components,” adds Cory Wohlbach, Teva’s Global Vice President Biosimilar Regulatory Affairs.

The manufacturing processes for these products can also be quite complex, explains Adrian Andrews, Senior Director EU Steriles Regulatory Affairs.

“For example, to produce a simple generics tablet you may have, say, five or six manufacturing steps but for some of the complex products we produce, there are up to 28 individual manufacturing steps.”

Many of the conditions that are effectively treated with complex generics are on the rise. The World Health Organization (WHO) says asthma affected an estimated 262 million people in 2019 and caused 461,000 deaths, while studies show that asthma rates have been surging around the globe over the past three decades, often attributed to pollution, climate change and global warming.

Approximately 24 million people, or one in 300, worldwide are affected by schizophrenia, according to the WHO, and about 1% of the world’s population will develop the disorder in their lifetime. 

The International Osteoporosis Foundation (IOF) estimates that osteoporosis affects one in three women and one in five men over the age of 50 worldwide, making it the most common bone disease and a serious public health concern. With the rapid ageing of the global population and the changes in lifestyle habits, the incidence of osteoporosis and related fractures has significantly increased and will continue to increase markedly in the future.

There is an urgent need to treat these conditions – however, therapeutic options remain limited. The FDA’s Center for Research on Complex Generics confirms that as complex generic products for complex medical conditions are harder to develop with traditional bioequivalence methods, fewer exist, resulting in less market competition for these products. Less competition means higher prices for patients or, in some cases, access to these products is denied. 

On a personal level for patients, one of the biggest advantages is that complex generics can reduce the number of medicines they have to take every day. From hypertension to schizophrenia, patients may struggle to maintain a complex dosing routine. Lidija Brnic, Teva Senior Medical Director and Head of Global Medical Affairs Generics, explains.

“Often patients with schizophrenia can be reluctant to take medication – non-adherence is a documented problem in the treatment of this condition. There is a role for complex products that only need to be taken weekly, monthly or once every three months rather than daily. The goal is to help support patients’ compliance with treatment, which is especially important for this condition.”

Fixed dose medicines are another crucial example of complex generics, used for the treatment of hypertension and diabetes for example, says Lidija.

“Combining two or more products in a single pill can be useful for treating these conditions so patients may need to take only one pill a day, instead of three.”

The lack of clarity around the regulatory pathway for complex generic drugs presents further challenges for these products when seeking approval to commercialize. Across the world, the regulatory requirements are often not well-defined, making it difficult to navigate the approval process. As a result, the length of time leading to the approval of a complex generic product can be significantly longer than for standard generics.

“There are only a few FDA guidance documents specific to complex generic drug development. This impacts a manufacturer’s ability to develop and provide the appropriate information to support timely approval of a regulatory application to commercialize a complex drug. It is essentially working in a vacuum,” says Janet Vaughn, VP Generics Regulatory Affairs North America. “Without specific guidance documents, FDA’s expectations are unclear and appear to be continuously evolving. This leads to longer approval times, thus delaying availability of these important drugs to impacted patients.”

A similar situation exists in Europe. “A gap in guidance for these types of products has long been recognized,” says Adrian Andrews. “So, it has been a case of us developing the guidance hand-in-hand with the regulators over the past few years.”

Despite the challenges, Teva is one of the largest producers of complex generics in the world* and had 21 generics products, including six complex generics, approved in the US in 2023. It had 21 generics products, including six complex generics, approved in the US in 2023. And of the three applications filed last year, two are potential “First to File” opportunities. In Europe, seven applications have been filed from 2014 to the present day.

Complex generics make up approximately 10% of Teva’s global generics pipeline – 26% in the US, 12% in Europe and 7% in international markets. Globally, complex generics deliver 29% of Teva’s total generics value (weighted average net present value), 50% in the US, 20% in the EU and 10% in international markets. Current products in the pipeline include long acting injectables, implants, inhalers, transdermals, topicals and sprays to treat a range of conditions including asthma, diabetes, osteoporosis and cancer.

“We are an innovative biosimilars and generics company with the technology and talent to develop generics that are not just small molecules,” says Cory Wohlbach. “We have the pathway set up and the know-how to get it done but the FDA review process takes a long time - one of our products has been going through the approvals process for nearly eight years, for example. You must have the necessary investment and patience to work in this area.”

It’s an investment and patience that Teva can amply demonstrate, driven by its purpose – we are all in for better health.

“Teva is one of the largest developers of generic drugs in the world. We have scientists who can develop all dosage forms and we have the regulatory knowledge to gain final approval,” says Janet Vaughn. “We strive to cultivate and maintain a close and positive relationship with regulatory agencies, as well as partner with industry organizations. We routinely recommend key areas for further research to support evaluation of generic drug equivalence and efficient development of generic drugs. We are in a strong position to make a difference in this area.”

The process of developing complex generics carries heavy risks but also promises great rewards for patients. The future looks promising.

*Based on IQVIA Midas data for 37 countries as of MAT Q3 2023