The Future of Complex Medicines: Development and Regulation

Highlights

• Scientific advances are enabling innovative therapies, such as CAR-T immunotherapy, gene therapies, biodegradable implants that deliver medicines to the eye, and biologic drugs that can be taken orally.
• Last year, Alnylam’s patisiran became the first RNA interference therapeutic to gain regulatory approval.
• The Nanotechnology Characterization Laboratory has characterized over 400 nanoparticle-based molecules in cancer and other indications, of which 14 are in clinical trials.

Innovation in Complex Therapies

Medicine has come a long way since the snake oils of the 19^th century. But even in the past two decades the complexity of medicines has evolved enormously, said Sesha Neervannan of Allergan — at least partly because most of the simple medicines have already been discovered. At the turn of the century, cell therapies such as CAR-T and gene therapies such as Luxterna, available today, were considered futuristic fictions.

Recently, the US Food and Drug Administration (FDA) defined complex medicines as products with a complex active ingredient, formulation, route of delivery, or dosage form, or that combine drugs and devices. But even a very simple product can become a complex medicine in a complex environment, Neervannan said. For example, a simple compound called cyclosporin, discovered almost half a century ago, gains complexity when used to treat an inflammatory condition called dry eye. That’s because it must reach the eye’s many different tissues, including the lacrimal glands, the cornea, and conjunctival tissue.

Researchers at Allergan are developing a biodegradable implant than can slowly release a glaucoma drug into the eye.

For decades, most eye disease treatments could only target the ocular surface. Researchers developed a procedure for injecting medicines directly into the eye about ten years ago, allowing access to the retina; but such intravitreal injections are highly invasive. Today, alternatives are emerging, such as biodegradable implants developed by Allergan that can deliver glaucoma medicine to the retina for six months. Many gene therapies are also in development for eye diseases.

The holy grail of complex medicines is oral delivery of biologic drugs such as antibody therapies. So far, such treatments are injected or otherwise administered invasively, but researchers are developing methods to deliver antibodies through the GI tract. Biologic drugs will continue to gain complexity, Neervannan said. As they do, other aspects of drug development, such as manufacturing, clinical science, and regulation, will need to evolve apace.

Regulatory Experience with ONPATTRO® (patisiran), a First-in-Class RNAi Therapeutic

Last year, US and European regulators approved the first RNA interference (RNAi) therapy, called patisiran, to treat a rare genetic disease called hereditary transthyretin-mediated amyloidosis (hATTR). Saraswathy Nochur, of Alnylam Pharmaceuticals, discussed how her company developed the medicine.

RNAi is a regulatory mechanism in mammalian cells in which long double-stranded RNA strands “diced” into fragments block the expression of specific genes. The researchers who discovered the mechanism, Andrew Fire and Craig Mello, received the 2006 Nobel Prize in Physiology or Medicine for their work. Alnylam, founded in 2002, targets RNAi to disease causing genes.

hATTR is caused by mutations to the transthyretin gene that causes the encoded protein to misfold and accumulate as plaques in the nerves, heart, and gastrointestinal tract. Patients become bedridden within 2.5-4 years and die in about 4.5 years, often of congestive heart failure. Patisiran, which is formulated as a lipid nanoparticle and injected intravenously, heads to the liver, where the gene is highly expressed and blocks transthyretin expression.

Alnylam first administered patisiran to people in 2012; the treatment diminished transthyretin expression by 85% in healthy volunteers. A year later the company dosed the first hATTR patients, seeing the same robust effect. A Phase III study conducted at 44 sites across 19 countries showed a long-lasting effect and clear patient improvement over 18 months. When the study concluded in 2017, Alnylam met with FDA officials, filed their results with the agency, and got priority review status, meaning the promise of a quick review.  “You need robust science-based development, high-quality regulatory submissions, and proactive and open engagement with the authorities” to gain regulatory approval for a new complex medicine, Nochur said.

Complex Drugs — The Future of Medicine

The Nanotechnology Characterization Laboratory (NCL) is a free, government-funded resource founded in 2004 that helps academic, industry, and government labs conduct preclinical characterization of nanomedicines intended to treat cancer. The number of clinical trials for complex drugs has increased dramatically over the past decade, and breakthroughs with more new compounds are on the way, says Scott McNeill, NCL’s director. For example, the lab has characterized more than 400 different nanomaterials and 14 nanoparticles they assisted with are currently in clinical trials.

Complex drugs are especially difficult to characterize because they generally consist of different but closely related structures, often with a range of acceptable characteristics such as size. Characterizing them requires identifying so-called critical quality attributes (CQAs), which differ for each complex entity.  Different components of the nanoparticle, its formulation, its route of administration, and other factors can all change the molecule’s biological effect, McNeill said.

The FDA requires industry to identify the critical quality attributes of complex drugs.

The range of molecular weights that make up the nanomaterial, its surface coating, and the presence of impurities are three key parameters for characterizing it. Results can change dramatically with small differences in formulation, McNeill said. For example, he recalled one batch of material in which the polyethylene glycol coating had dissociated from the particle, causing toxicity. Another feature that can cause toxicity is the presence of lipopolysaccharides, which affects about 30% of samples that come into the NCL. Overall, said McNeill, characterizing the features of nanoparticles and their drug release properties is significantly more challenging than characterizing small molecules.

Highlights

• Complex drugs cannot be fully characterized, so regulating them consistently has been a challenge.
• The frameworks for regulating nonbiologic complex drugs are emerging in Europe, but it would help to be able to assign different kinds of medicines to formal classifications.
• Health Canada is in the process of developing specific regulations and policies for approving complex medicines.
• The tools, guidance, and definitions for approving complex medicines at the FDA are continually expanding
• It may not be possible to determine the “sameness” of some follow-on products, but regulators can instead focus on “prescribability” or, the product’s clinical value.

Introduction to the Importance of Regulatory Science

“Regulatory science is a critical bridge between basic science discoveries and the marketed therapies they yield,” explained Vinod Shah, of the Non Biological Complex Drugs Working Group. Applying regulatory science to nonbiological complex drugs is complicated, however. These molecules cannot be fully characterized, and the manufacturing process defines their identity. “The process is the product,” said Shah. That has meant that in some cases, such as the approval of cancer chemotherapy agent doxorubicin, a biosimilar version of the drug is approved by some regulatory bodies but not others. Stakeholders will need to work together to advance both the science and the regulations around such products, he said.

EU Regulatory Perspective on Complex Medicines

In Europe, the regulatory framework for non-biologic complex drugs is well established for novel products, but is distressingly inconsistent for their follow-on products, said Beatriz Silva Lima of the University of Lisbon. Follow-on products in Europe can be approved as generics, as hybrids, or as biosimilars, but the process is inconsistent in assigning different drugs to these categories.

No formal classification exists for nonbiologic complex drugs, but many such compounds have been approved.

Europe has been creating guidance for nanomedicines-based formulations through an ad-hoc Nanomedicine Expert Group, which met several times between 2009 and 2015 and succeeded in establishing some scientifically based guidance. However, efforts stalled after 2015. Currently, because there is no clear definition of what constitutes a complex medicine, a product cannot receive a formal classification. Medicines are currently classified as small molecules, biologics, or advanced therapies, and there is not enough nuance in these categories (particularly the last one) to establish clear requirements for approval, said Silva.

Silva discussed the regulatory pathway for two different follow-on products seeking approval in the European Union: the anemia treatment iron sucrose and the cancer chemotherapy agent doxorubicin. The first regulatory discussions for iron sucrose occurred in 2010, but data on safety and key attributes published subsequently was controversial. For example, researchers reported that similar plasma concentrations of the follow-on products may not lead to similar activity. However, several iron oxide containing particles were approved. Meanwhile, market authorization for a liposomal formulation of doxorubicin was withdrawn because some tested did not align with doxorubicin medicines already on the market.

Scientific and Regulatory Challenges with Complex Generic Medicine

Twenty-first century medicine is a paradigm shift, said Akm Khairuzzaman of the FDA. Drug developers are moving from small molecules to DNA- and RNA-based therapies; personalized medicine provides an alternative to a one-size-fits-all approach; 3-D printing is providing a new avenue for bulk medicine manufacturing and making on-demand products; and medicine is getting digitized in chip-in-a-pill therapies. This paradigm shift creates both scientific and regulatory challenges to approving generics based on this new wave of novel and innovative therapies.

The FDA doesn’t have a formal definition of complex medicine, but the approval of generics relies on demonstration of shared identity with the original therapy. Based on that, efficacy and safety can be inferred. But characterizing sameness of active pharmaceutical ingredients in complex products is challenging.

The FDA’s definition of complex medicine is evolving, but it involves several possible components.

For example, liposome formulations can improve local efficacy and reduce systemic toxicity. However, the free drug is released as liposomes break down; it’s unclear which to measure to determine efficacy and impossible to determine precisely how much of the drug is retained by the tissue in vitro. For drugs delivered to specific locations in the body, quantifying low levels of drug in plasma is challenging.  And when determining equivalence of complex generics with a device component, it can be unclear when design characteristics affect the therapy’s dose, release rate, or other features.

In order to solve these problems, the FDA has provided new guidelines for generic manufacturers to engage with the agency early in the process. The tools for evaluating complex generics are continually expanding, Khairuzzaman said. And as more and more product-specific guidance on complex generics become available, that too will help define the path.

Complex Drugs — the Health Canada Perspective

Currently, Canadian regulators do not have a specific guidance or definition for complex drugs, said Michael J.W. Johnston of Health Canada, the country’s regulator for health and consumer products. Such medicines are approved on a case-by-case basis and decisions are made based on pre-market assessment and post-market surveillance, as well as additional information that becomes relevant as understanding of these products evolves. Health Canada does, however, have a working definition of nanotechnology and in 2018 it revised its guidance on products at the drug-device interface.

Using its current approach, Health Canada has approved several products that could be considered complex drugs.  These include five liposome-based products, a protein nanoparticle, an antibody-drug conjugate, and three PEGylated proteins. Because many of these products were approved several years ago, Johnston said, the agency has already approved two follow-on complex products and expects to see more applications. Johnston encourages developers of both innovative and follow-on complex medicines who seek approval in Canada to reach out to regulators early in the process. Health Canada uses guidance documents from other regulatory agencies in its decisions and is actively involved in international harmonization efforts.

The number and complexity of complex medicines is likely to increase, so Health Canada is in the early planning stages of developing specific regulations and policies for their approval. Several other ongoing initiatives, such as multiple nanotechnology working groups and efforts to develop liposome and protein nanoparticle reference materials, may strengthen approval processes for complex products.

Science-driven Regulations for Complex Drugs and Necessity for Harmonization

Harmonizing the regulatory processes for complex medicines will require the participation of open-minded regulators willing to listen to scientific justifications for changes to the current system, said Henning Blume of SocraTec R&D and the University of Frankfurt. Complex medicines are not a homogenous category, so they cannot be uniformly regulated. Instead, they will require product-specific guidance.

Encapsulated and “free” doxorubicin has very different characteristics.

Blume described how US and European regulators deal with four complex products: liposomal doxorubicin, glatiramer acetate, low molecular weight heparins, and iron sucrose. He also discussed whether the current requirements were scientifically rational. For doxorubicin, an anti-cancer agent, regulators in the US and Europe require drug makers to show bioequivalence for both encapsulated and unencapsulated drug. However, only the encapsulated form of the drug as measured in plasma reflects its biopharmaceutical properties, so this is the only form that should be measured.

For glatiramer acetate, an immunomodulator used to treat multiple sclerosis, it is near-impossible to determine whether a follow-on product is the same as the original because the drug consists of an unidentified number of protein components. That means it may not be possible to develop an adequate generic form of the drug. For low molecular weight heparin, a blood clot treatment, and iron sucrose used to treat anemia, FDA and EMA assessed different aspects and characteristics to draw conclusions about the slippery concept of sameness.

Overall, Blume concluded, confirming sameness in complex medicines is often difficult or impossible, which makes it challenging to assess generic medicines. A better approach might be to assess what Blume calls “prescribability,” which refers to whether or not the product can be effectively prescribed.

Highlights

• Expanding the use of real-world data and evidence can dramatically boost regulatory efficiency.
• New mechanisms are needed to decrease the burden of approving biosimilars and thereby improve the sustainability of health care.

Supporting Drug Development and Higher Value Use with Real World Data and Evidence

Regardless of how we define complex drugs, they are is expensive, said Gregory W. Daniel of Duke University, in his keynote speech. That means society must strike a balance between incentivizing innovation and making the fruits of this innovation accessible to patients. Drug prices in the US are rising, due in part to medicines such as the $850,000 gene therapy Luxturna, which treats a rare eye disease. Yet these medicines transform patients’ lives. “We shouldn’t expect that to be cheap,” said Daniel. “The question is, how should we deal with that spending, and what is too high?”

A blueprint for lowering drug prices announced last year by the US government proposed improving competition; bringing down list prices of physician-administered drugs; and establishing value-based payment approaches, in which insurers pay more for drugs that work than for drugs that don’t. Another key way to reduce costs without addressing drug pricing, though, said Daniel, is to reduce waste — such as unnecessary services. He described ways to do that using real-world data generated when people use the health care system. Such data — from when a patient sees a physician, gets a prescription, triggers an insurance claim, or wears a device that collects information about her health — can be used to build real-world evidence for effective health care decisions and policies.

Real-world data and evidence can improve efficiency and cost-savings in several aspects of drug development and health care.

Although a large volume of real-world data and evidence exists, it is poorly curated and therefore greatly underused. Daniel described a few areas where it is used. For example, this data can make clinical trials more efficient by identifying appropriate patients and thereby increasing the efficiency of recruitment. It can also be used to support regulatory decisions by helping to identify new indications for a drug. To expand the label of a medicine for breast cancer, which was approved in women, Pfizer mined electronic health records and post-marketing reports from patient databases to show that it was safe in men.

The 21^st Century Cures Act, passed in 2016, required the FDA to set up a program evaluating how to use real-world evidence in regulatory decisions. The FDA has used such evidence in the past, but not consistently. For example, the FDA has occasionally allowed trials for rare diseases to compare patients taking a new drug to historical controls — past patients in a database who received a standard therapy — when a randomized controlled trial was not feasible. The administration also uses data collected by drug manufacturers after the drug is on the market to monitor safety. However, it rarely uses real-world data and evidence to expand indications or populations for which an approved drug can be used. “That’s the big sweet spot for real-world evidence,” said Daniel, because it can provide patients and regulators with clinically useful information, at much less expense than conducting an additional clinical trial.

In December 2018, the FDA published a framework that laid out three issues with using real-world data and evidence. First, it can be difficult to determine the quality of the various sources of such data. Second, if observational studies are used instead of randomized trials, steps must be taken to reduce bias in the selection of subjects. And third, care must be taken that real-world data and evidence aligns with the agency’s existing data collection requirements.

Daniel concluded his talk by discussing issues with value-based pricing. It is particularly alluring for the current wave of complex therapies because it often consists of a single, extremely high-cost intervention. However, he said, historically value-based payments have not resulted in cost savings, and current legislation makes most such plans unworkable. Daniel’s institute is exploring ways to make them more feasible.

The Morality Gene — a European Perspective on Collective Sustainable Action

Sustainable solutions to global health care challenges will involve increasing patient access to affordable biologic drugs, said Florian Turk of Sandoz Biopharmaceuticals. Introducing biosimilars is a key way to do that. For example, the use of biologic anticancer medicines increased by 150%–800% when biosimilars became available. Yet so far, no country has fully unlocked the potential of biosimilars because of complicated approval processes. And although newer biosimilars are being taken up quickly, the rate of uptake for these medicines varies widely across different countries.

Uptake of biosimilars varies widely.

In 2006, Sandoz became the first company to receive approval for a biosimilar called Omnitrope. The current wave of biosimilars often requires the submission of more data to regulators than the original drugs they copy. This is because regulators’ expectations of what should be measured have increased, Turk said. That raises the question of whether or not the use of biosimilars to expand patient access is sustainable. The problem is even more acute in the US, where just 18 biosimilars are approved, compared to Europe where 55 are approved.

Despite approval challenges, biosimilars save $60 million annually in health care costs in Europe. The US, on the other hand, has not achieved significant savings from the use of biosimilars. Turk referred to the situation as “a typical tragedy of the commons problem.” Companies act in their self-interest by pushing their products to the market while regulars and payors do so by pushing burdensome but scientifically unnecessary requirements. All of this is done at the expense of the common good, which would be better served by embracing biosimilars more fully. Somehow, said Turk, the system must acquire better practices–which he compared to “genes” mutated to increase an organism’s fitness–in order to achieve sustainability and contribute to the collective wellbeing.

Highlights

• GoNanoBioMat is a framework that allows researchers to pinpoint safety issues in all stages of the nanomedicine development process.
• Improving access to medicines will require fixing the regulatory system to facilitate the approval of biosimilars.

Implementing the Safe-by-design Concept to Polymeric Nanobiomaterials in Drug Delivery

A lot of money has been invested in developing nanomedicines, and a lot of data have been produced, but so far, few nanomedicines have been approved. Cintia Marques, of the University of Geneva, described a European consortium, GoNanoBioMat, which aims to speed and support the development of nanomedicines by applying an approach called Safe by Design. Within the GoNanoBioMat framework, researchers can identify when a nanoparticle is unsafe or inefficient, or when it has unwanted side effects at any stage of the development process from material design to storage and transport.

GoNanoBioMat is a framework in which researchers can identify when a  nanoparticle is not safe or efficient, or where it has unwanted side effects, at any stage of the development process.

Marques described her experience trying to design a chitosan nanoparticle that encapsulates insulin. Chitosan is a family of biopolymers with strong characteristics for use in nanomedicine. However, when she and her colleagues dove into the literature, they found that many key characteristics were not well-defined. Inconsistency between papers made comparing results impossible, and key knowledge gaps existed in the substance’s immunoactivity. Differences in the characteristics of insulin from different sources compounded the problem. The Safe by Design guidelines gave them a context in which to identify the problems and systematically address them, she said.

Connecting the Dots: Global Development of Complex Drugs and Biosimilars using Consistent Science to Enable Efficient Regulation

The science underlying new drugs is not sufficient enough to ensure access to medicine, said Gillian Woollett of Avalere Health. Health burdens rarely match scientific progress as there are disproportionate incentives for medicines that will benefit the fewest people. That is especially true for biosimilars — if their approval could be facilitated, they would significantly decrease health care costs and make the most powerful medicines more accessible.

Biosimilar sales are a tiny portion of total sales of biologic drugs.

The US — 5% of the world’s population — has 60% of the market by dollar value for all biologic drugs. Europe, meanwhile, has 90% of the biosimilar market, but that market is still very small. It is less than 1% of total biologics sales. That means that biosimilars are introducing competition, but not getting market share. And that is a key problem, according to Woollett. Nearly a thousand biotech medicines in development have actually been tested in people, but rarely if ever have more than six new biologics and a few biosimilars been approved in a given year. “This is a broken regulatory model,” Woollett said. There is no scientific reason for different regions to require different data for approving biosimilars. Thus, the process of harmonizing regulations worldwide must be accelerated. Currently, regulators are asking sponsors to reinvent the wheel.

The assumption for biosimilars is that it is difficult to prove they are similar to the products they are based on; but in fact, the original products can also vary batch to batch. The requirements to prove that a biosimilar and its original drug are interchangeable are excessive. For example, the cost to get a biosimilar approved is 100 times the cost to get a generic small molecule drug approved. That kills companies’ return on investment and thereby discourages the process.

Highlights

• Real-world evidence could potentially be leveraged not just to expand indications of approved drugs, but also to facilitate the development of novel medicines or follow-on biologics.
• Inequality in access to medicines is likely to increase unless stakeholders can communicate to reign in costs.
• Currently, one can produce much more information than can be used in regulatory decisions.

To start the panel discussion, Daniel proposed that real-world evidence could be leveraged not just in post-market studies but also before an investigational new drug application is filed. In order to design the best possible study, it’s important to understand the real-world situation of patients. It would be helpful for companies to be able to hold private communication with regulators early in the development process about how such data could shape the protocol of studies needed for approval.

The biggest limitation to the use of real-world evidence, Daniel explained, is that the infrastructure that links and curates data from different sources does not currently exist. Even different departments within a single hospital record information — say, whether a patient received a particular medicine — in different ways. Integrating hospital data with insurance claims, patient self-reports, and other data is an even bigger headache. But those systems, such as the FDA’s Sentinel system, are gradually being built. Crommelin pointed out, too, that our ideas for what makes good data will also evolve as this infrastructure comes into being.

The panel also laid out how they envision the regulation of complex medicines might change in the next 5–10 years. Neervannan said that the world is becoming ever more digital and expectations for quality of life are rising, so many of today’s problems might be solved by then. But, he added, “unfortunately, one of the side effects of living is death” and so new problems will emerge for the industry to address. Daniel predicted a world in which we will have figured out how to pay for gene therapies and provide economic incentives for antimicrobial drug developers, but where reducing overall spending will still be a problem.

Woollett noted that science is cumulative, so it is always going to be the best it’s ever been, but that inequality in access to healthcare was likely to increase.  Currently, cost in the US healthcare system is managed by delaying specialty care as long as possible, which isn’t good for patients. What’s driving the problem, she said, is the lack of translation between disciplines — for example, what is legal, what is economically desirable, and what is scientific, “We are losing out on the collective good because we are not hearing each other,” she said. Turk, meanwhile, noted that the next decade will see a fundamental change in funding models for complex curative therapies and in ways to sort through the immense amount of information that today’s advanced science can yield.  Those changes, he said, are likely to come from ideas brought in from completely different fields.