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Navigating Regulatory And Development Milestones In Biopharma

Research scientist receiving drug approval virtual

The biotherapeutics market is evolving, and emerging companies are advancing cutting-edge therapies to keep pace with innovation. The potential for life-changing, curative solutions where limited options exist makes this an exciting time to be in biotech. Although patient focus is constant, regulatory concerns and investment capital needs evolve as biopharma startups move their products from development to approval.

This article addresses how early-stage biotherapeutic companies can avoid common pitfalls and access support as they navigate the funding and regulatory processes to bring novel therapeutics from research to market. The thought leaders participating in this forum are working to develop viral vectors, cell and gene therapies, and bioengineered vaccines.

Frost & Sullivan recently invited industry leaders with experience working with drug development regulatory challenges to participate in a thought leadership forum. This forum brought together leading minds in this dynamic field to discuss regulatory challenges inherent in the development of therapeutics.

Challenges and opportunities in drug development

Biologics drug development efforts and processes have evolved significantly since the approvals of replacement protein-based drugs like growth hormones and insulin. New methods and technologies, such as advancements with fusion proteins, gene constructs, and highly engineered antibodies, are using more complicated formulation processes than were needed for earlier replacement protein biologics. These new technologies bring challenges inherent not only in the lab but also with global  regulatory agencies reviewing and approving them.

Companies entering the biopharma business arena face high barriers to success, not only in the clinical development processes with the therapeutic, whether drugs or gene and cell therapies, but also with regulatory, manufacturing and investment-capital obstacles. Though manufacturing small quantities of product may be easily done in a laboratory, the scale-up for human trials is a completely different situation.

Global regulatory agency involvement

Global regulatory agencies in different countries handle communications differently. These expert panelists said that in the US, the FDA has a wonderful track record of discourse with the companies. Regulators in both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are open to sharing experiences from products that have come across their desk with other gene and cell therapies. In the EU, the Paul Ehrlich Institute is also open to meetings.

Japan’s Pharmaceutical and Medical Devices Agency (PMDA) works a bit differently. Discourse must occur prior to the meetings between the company and the agency. Before agency meetings, companies have the opportunity to ask many questions. The PMDA has three phases in its review process: 1) Preclinical to quality; 2) Manufacturing; and 3) Clinical. For each segment, companies have the opportunity for a pre-consult and then a formal consult. The submissions in Japan must be written in Japanese. The written language requirement adds a layer of complexity for US and European companies.

China has its own regulatory submission process. The experts noted that China has had to tighten up and meet the global standards for clinical development and regulation of clinical development. It has not had a lot of experience with cell and gene therapies, and Chinese regulatory bodies sometimes require more insights from the company doing the submission.

Early development

The complexity and high variability of biology related to biotherapeutics bring challenges to the process at all stages of development. Early development research projects typically involve the use of smaller amounts of material product. Often, when moving from the research and development stage to the clinical stage and converting from research-grade material to good manufacturing practices (GMP)-grade material, the difficulty of transferring from a preclinical model to clinical trial material is not always seamless. Patricia Lawman, CEO of Morphogenesis Inc., said, “When you think about injecting something into a person, it takes on a whole new shape.” With human trials, she said, “How the manufacturing facilities are set up, what personnel and equipment are needed and what training is required all become important since GMP-compliant processes are now required. Everything has to be validated and locked down. We needed to find a balance between what is critically needed versus what can be done later in the development, so we hired experts to help us through this segment.”

Cell and gene therapies currently in development often target rare diseases, hard-to-treat cancers, and genetic defects. The panelists noted that viral vector-based therapeutic vaccines require occasional changes in promoters or other genetic changes that sometimes alter the characteristics of the products. These changes could affect the safety and efficacy profile of the product and could require bridging studies as part of the various regulatory filings. Minimal animal testing is necessary for gene therapy medicinal products (GTMP) prior to any human trials, because the bio-distribution and dissemination of viral vectors to target tissues or organs cannot be studied before introducing a GTMP into humans.

Mukesh Kumar, CEO of FDAMap said, “When moving from R&D stage to clinical stage, converting the research-grade material to GMP-grade material is very challenging. If you are going to do a phase 1 study, you don’t want to bankrupt yourself in the transition process doing things that do not need to be done until later stages. From R&D to clinical manufacturing is the hardest to do. Once you get to clinical production, you will think about SOPs and validations and it will get easier. The first transition, however, is the hardest.”

The experts stated that sometimes the FDA has no precedents to follow with some of the preinvestigational new drug (IND) cell and gene therapy work, because some therapeutic cancer vaccines, particularly those based on novel platforms, have never been seen by that regulatory body. The FDA is open to having conversations with the Chemistry, Manufacturing and Control (CMC) teams and to asking a lot of questions. Pre-IND discussions with the FDA are critical to learn how FDA would be looking at these products. CMC teams inside companies are encouraged by the CBER officials to ask many pre-IND questions. Officials discuss process development evolutions with the CMC teams to understand what is happening.

Clinical trials – phase 1

First-in-man trials, phase 1, are intended to not only identify the optimal dose but also establish a drug’s safety, tolerability, and pharmacokinetics in groups of healthy volunteer subjects.

According to Kumar, there are fewer challenges with phase 1 first-in-man trials than in other phases. Lee Buckler, President and CEO of RepliCel Life Sciences concurred, saying that “for genetically modified cell therapies, the standards for going from preclinical to phase 1 are low compared with many drug programs.” Lawman added, “The challenge with phase 1 early-stage human trials is to get the safety and efficacy data to be able to move forward to phase 2. Many times, decisions are being made with regard to monotherapy versus complicating things by adding different combinations.”

With cell and gene therapies, small changes to the process can make big changes to the product. The experts agreed that it is best to get any product changes out of the way as early in development as possible so there is just fine-tuning when you get to the efficacy trials. There will always be a temptation to continuously improve the product, which you can’t do once the trials are underway and efficacy signals are seen.

Besides identifying the correct dose, another challenge in a phase 1 study is the lack of full characterization of chronic toxicity since typical maximum tolerated dose (MTD) determination methodologies reflect only cycle 1 toxicity. This could misrepresent the safety profile of a cancer therapeutic agent that is administered over more than one cycle. Further, for some targeted therapies, toxicities are delayed and assessment of a tolerable dose during cycle 1 is not feasible (1).

Clinical trials – phase 2

Phase 2 trials can be divided into phase 2a and phase 2b trials. Phase 2a trials are sometimes referred to as ‘proof of concept trials’ and investigate frequency of dosing, dose response, and type of patient treated. Phase 2b trials could be referred to as ‘pivotal trials’ with the goal of demonstrating a drug’s efficacy, particularly for rare diseases. Phase 2 usually involves 200 to 500 patients, though much smaller sets of patients are involved with orphan or rare diseases and cell and gene therapies. Regardless of the patient numbers, the ultimate goal of phase 2 is to determine a drug’s efficacy.

Lawman remarked that it is challenging in early human trials to get the efficacy data along with the safety data. Dose optimization and improving efficacy are a balancing act. One main obstacle to selecting an optimized dose is the absence of clinical data from multiple dose level studies, where both safety and efficacy had been evaluated. Further, Lawman said, “investors want the human data, the numbers and the statistics and milestone delineations, prior to investing. We have to figure out ways to convey to these investors that there are clear milestone delineations, even if we are not sure what they really are. In phase 2, we are constantly thinking about, should we go with a monotherapy or complicate things by making different combinations?”

Kumar noted that, typically, “phase 2 is the most challenging clinical phase. In phase 2 trials, you see a lot of things that no one worried about in phase 1 and that one would not want to investigate in phase 3. Kumar added, “By phase 2, it is very important to lock the product defined and characterized as early as possible. If you are still tweaking the product, especially in the cell and gene therapy area, and do not know how much will need to be manufactured per patient, it will be miserable.”

Buckler added, specifically with cell and gene therapies, “phase 2 is when you are pressed with mechanism of action and dosing questions, which may require several development steps for the process. It is not uncommon at all to require multiple phase 2 trials to get the answer on dosing and treatment protocols as well as the efficacy data needed. And so we’re thinking about closed systems and automation where possible, and evolving the manufacturing to lower the cost of production wherever possible to increase consistency batch-to-batch, all of those things that you need research inputs into, but also that discipline of bioprocess engineering, which is very different from research and clinical development. And that’s a whole expertise in and of itself that one has to bring to the clinical development process.”

Some companies working with cell and gene therapies have reported completing the manufacturing of the clinical trial material in-house because it gives the company the greatest opportunity to understand their product as early as possible.

David Boisvert, Senior Director of CMC, Arch Oncology noted, “the biggest regulatory challenge is for the entire team, on both the CMC and clinical sides, to think together on the strategy and key points for the molecule to articulate how it is working. There needs to be solid communications strategies, internally and externally, for products.”

“Phase 2 trials have the highest failure rates of any of the three clinical trial phases,” Brad Rosenblum, CFO, Life Sciences, BMR Financial Consulting, said. “It is often referred to as the riskiest phase for a number of reasons. When seeking financing for trials, it is a numbers game, making sure companies have enough capital to get to the milestone and all costs are covered to minimize risks.”

Boisvert added, “When you’re in multiple global jurisdictions like we are, the time to establish the proper communication strategy is of course critical to clinical development, which is even trickier because, whereas the same clinical trial in the US and Europe might be nothing more than a phase 2, it’s that same trial in Japan that has a very good chance of being approved of.” Buckler said, “It could be the trial which gets a conditional approval and moves to market launch. So we want to start thinking about that early as we transition into such a trial in Japan. And then take those lessons and that evolution into our phase 2 and pivotal trials elsewhere.”

In addition to being the most the challenging phase, phase 2 is also the most important phase, said Kumar, “because if you get good data at phase 2, you can also receive important FDA designations, including breakthrough therapy and, at times, accelerated and fast-track status, as well as a lot of other incentives. Incentives come with a lot of strings attached. It is the most risky but also the most rewarding phase of clinical trials.”

“Obtaining sufficient investment capital always depends on what stage you’re at, what you are looking to raise, and what you view as the milestones,” said Rosenblum. “That does, at times, require a lot of conversations with the investors, both current and potential. It really just comes back to the basics of clinical evidence, safety, data validation, and what is your pathway to de-risk the development of the asset as it is being funded over time, and also to get to that IND phase 1 and phase 2, etc..” He added, “There is a little bit of difference I see between strategic investors and the institutional, financial investors. Depending on the strategies, some want to get in very early, others may require more progress or data to really understand where the asset is to make an investment. It is important to know what you can deliver with an asset and what are the milestones that everybody will agree on.”

Clinical trials – phase 3

Phase 3 trials are predominantly large, double-blind, randomized, and placebo-controlled, to further test efficacy and look for side effects. Large patient populations are typically used for most drugs to obtain statistical significance; however, trials for rare diseases and cell and gene therapies are often much smaller.

The panelists agreed that challenges with phase 3 rest not so much with the clinical trial design, but rather, the approval endpoints. A tremendous amount of time is often spent in negotiation with global regulatory authorities at the FDA, EMA, and PDMA to get these endpoints identified.

Outsourcing trends

Small biotech companies seeking expedited regulatory pathways and short amortization periods support outsourcing. Although some companies eventually bring commercial production in-house, it is mainly due to contract development and manufacturing organization (CDMO) capacity shortages. Many with in-house capacity still dual-source as a complementary source of supply (2).

The panel consensus was that the use of CDMOs involves trade-offs between doing the manufacturing yourself and learning a lot of valuable lessons versus using a CDMO that could potentially lower your costs. Collaborations between companies can sometimes bridge the knowledge gaps. Several panelists do use external experts, contract research organizations (CROs), and CDMOs for clinical trial management, gap analysis, regulatory advice, and manufacturing. The main reasons are that it is capital- efficient and they do not have to employ full-time work for these individuals, as there is no full-time workload for quality assurance (QA) or regulatory. External experts can help move things forward efficiently.


Several approaches have been taken to help startup companies meet the growing need for regulatory processes and clinical development in biologics, including cell and gene therapies. Multiple factors need to be considered such as the type of technology being developed, the transition from research and development to clinical trials, the need for non-clinical testing, the manufacture of the product, discussions with regulators, and global versus local development of the product. Companies big and small deal with these issues with a combination of internal and external resources. While much can be done internally at the company in the early stages of development, large clinical trials, large-scale manufacture, and commercial release often require outsourcing to vendors. Considerable momentum has been observed when combining in-house with outside expert consultant talent.

An expedited regulatory pathway, short amortization, and technology evolution all support outsourcing. Some companies often struggle to determine if they should hire full-time employees or use vendors for specialty areas of expertise such as quality assurance and regulatory affairs. There is a shortage of trained full-time equivalent (FTE) staff to fill all available open jobs in the areas of QA and regulatory. Although some companies can internally address the challenges inherent in the different phases of drug and biologics development, CDMOs are viewed as a complementary source of expertise for even these companies.

The current clinical pipelines and number of clinical trials in the cell and gene therapy area requiring clinical-stage manufacturing are increasing. Expedited approval pathways under breakthrough or fast-track designation also mean shorter development times and faster times to approval and commercialization. As the industry develops and new technologies drive manufacturing costs, volume demands will continue to increase. The panelists concur there will be a balanced mix of manufacturing strategies between outsourcing and in-house, based on the sizes of pipelines and available talent.

Additional participants not quoted in the article are Graciella Beyers, Senior Director Project & Alliance Management, miRagen Therapeutics Inc. and Karin Thacker, VP, Global Regulatory Affairs, Gritstone Oncology.

1. Yan J, Jin JY, Hyman DM, Geoffrey K, and Suri A. Clin Transl Sci. 2018;11:345-351. doi:10.1111/cts.12540 C 2018
2. (i) Designing a Customer-Centric CDMO, by Patricio E. Massera, pharma’s almanac, May 24, 2019 (ii) Outsourced Pharmaceutical Manufacturing 2020, Current trends & future prospects, Results Healthcare, November 2019- link

Post-event survey

We posed five questions to the panelists. Here’s their take on some of the big challenges in developing viral vectors, cell and gene therapies, and bioengineered vaccines.