David Shoemaker, PhD

While the field of gene transfer has been active and evolving over the past 30 years, there are only a handful of products that have recently become approved gene therapies. Most product developers believe that gene transfer is now at a tipping point, but realize it will require a close coupling between the accumulating scientific knowledge and the therapeutic target product development expertise to generate approved gene therapies at an increasingly rapid rate. Although it is an inaccurate term (nothing is a therapy until it has market approval), gene therapy has become a ubiquitous term to refer to gene transfer products and the more recently discovered gene editing (e.g., CRISPR) products in development.

	Gene transfer products are meant to treat diseases resulting from lack of a gene’s functional protein product. The gene addition can be accomplished either by 

(vectors and other delivery vehicles) or 

(manipulation of a patient’s own cells and reinfusion) techniques. Both 

 gene addition techniques are currently at the forefront of science, which explains the paucity of marketing applications that have been submitted, let alone approved, in recent years.  Gene editing products in development are meant to alter the existing gene, thereby conferring efficacy and not add a new functional copy of the gene; but none of these have been approved as of yet.

	Over the last several years, gene therapy technologies and products have primarily been developed by biotechnology companies, academic laboratories, and government laboratories as large pharmaceutical firms have evolved to marketing and sales companies by divesting themselves of a great number of research scientists and licensing in these technologies from other entities. However, few academic or government organizations are experienced with the entire product development process, including bringing a product to market. Therefore, there must be a coordinated effort and close collaboration between academia/government and biotech development talent to access both scientific and product development knowledge required for a program to be successful.

	Updated FDA guidances provide clarity and require more information 

	While gene therapy products provide potential for exciting breakthroughs, they are also extremely complex to develop for the market. This complexity has prompted the FDA to recently release additional guidances to help move these products forward. Early FDA gene therapy guidances include traditional investigational new drug (IND) requirements and Phase I good manufacturing practice (GMP) guidance. Two of the six 2018 gene therapy guidances are related to requirements for long-term follow-up monitoring and other clinical study design considerations, as well as chemistry and manufacturing and controls (CMC) procedures and practices to ensure safety. This is not surprising inasmuch as regulators have been concerned about the safety of gene therapy products from the inception of this field due to the lack of complete understanding of the science surrounding these products.

Considering there is no track record for the administration of these products, companies should be aware of these guidances and budget for extensive follow-up (e.g., five years) for their clinical study subjects and potentially even the patients treated with their product after it is approved to determine the eventual safety profile and durability of the therapeutic effect. As far as manufacturing concerns go, new cellular-mediated gene therapy products will require many different materials during the course of their journey-from the harvesting from the patient or donor, through manipulation and testing, and into the patient. Hence, a comprehensive list of the materials used in the process and a description of their quality and suitability must be included in the regulatory submissions.

	Since most gene therapy products are targeted for life-threatening or serious orphan diseases with unmet medical needs, the clinical plan will, in all likelihood, be expedited relative to the traditional clinical plan for a product intended to treat more conventional diseases. This acceleration requires early and more frequent interaction with regulatory authorities to ensure agreement on such things as 1.) novel clinical endpoints that convincingly demonstrate clinical benefit; 2.) biomarkers or other endpoints that could potentially be used as surrogate clinical endpoints; 3.) collection of data reflecting the natural history of the disease from the literature, real-world evidence, or via the conduct of a 

 natural history clinical study; and 4.) patient-reported outcomes focusing on quality of life metrics that matter to the patients or their caregivers, all of which can contribute to the totality of the data regulators will integrate to ultimately reach their decision on marketing approval.

	One of the main takeaways from the updated FDA guidance is the need for a strategic CMC development plan, because if the product cannot be manufactured safely, then clinical studies will inevitably be delayed. For gene therapy products, CMC work often ends up being a rate limiting step in preparing for the initial IND as well as the eventual marketing application submission of a gene therapy product.

	A comprehensive CMC plan is also important because the FDA places a greater emphasis on the quality portion of the submission for gene therapy products than for traditional therapies. In a 2018 interview with former FDA Commissioner Scott Gottlieb, he stated, “that for most standard drugs, traditionally 80% of the review process is focused on clinical aspects and only 20% on quality or is CMC related. For gene therapy products, those numbers are reversed.” From this, sponsors and CROs can be sure that the CMC modules in their submission must be comprehensive to obtain regulatory approval.

	Consider an INTERACT/pre-pre-IND meeting

	Some products need to be discussed early with the FDA so that sponsors have buy-in from FDA on their proposed development plans. If eligible, sponsors should take the opportunity to sit down with the FDA in an INTERACT meeting (aka, Initial Targeted Engagement for Regulatory Advice on CBER products; previously known colloquially as a pre-pre-IND meeting). This interaction is used to educate the FDA about the sponsor’s product and familiarize the agency with the science behind it and help FDA understand the rationale behind their integrated product development plan. These meetings also can be crucial in helping obtain agreement for the preclinical program. Additionally, sponsors should use the INTERACT meeting to get clarification on CMC aspects related to specifications, controls, as well as what steps they want to see in terms of the manufacturing process.

	In summary, the only way to move some of these gene-based products forward quickly is with more FDA interaction than is usually recommended for developing products. The guidances issued thus far are not sufficient to enable a company to make much development progress without interacting with the FDA. By asking the correct questions at regulatory meetings and listening carefully so product sponsors may coalesce bits and pieces of information, the FDA has learned from other gene therapy sponsors that have submitted INDs and bioligics license applications (BLAs) for gene therapy products. The FDA is unable to breach confidentiality with product sponsors, but they will comment much more intelligently as a result of its experience with many of these products.

	When one looks at the remarkable efficacy that some gene therapy products are providing, it also makes sense for the agency to prioritize and expedite gene therapy guidances and help sponsors develop treatments that can make a difference. However, if a company’s development team comprises individuals who both understand the science supporting these novel products and are experienced with the guidances and regulatory precedents established for previous product approvals in these or similar indications, a gene therapy program may ultimately make it to market.

, PhD, is Senior Vice President, R&D, Rho Inc.

Articles

Navigating the many complexities in clinical trials, manufacturing, and regulatory interaction in moving gene therapies from development to market.



The Gene Therapy Product Development Process

	With the passage of the Biosimilar Price Competition and Innovation Act (BPCIA) in 2009, the U.S. created new pathways for development and approval of biosimilar and interchangeable products [Section 351(k) of the Public Health Service (PHS) Act (42 U.S.C. 262)], in the hopes of creating a low-cost alternative to expensive, innovator-marketed biologics whose patent terms were expiring. The BPCIA was intended to be a major cost-containment mechanism of the Patient Protection and Affordable Care Act of 2010. The origin of the BPCIA had its roots in the Drug Price Competition and Patent Restoration Act (DPCPRA) of 1984 championed by Senators Waxman and Hatch, which has provided low-cost generic alternatives to prescription brand-name drugs for the three subsequent decades. What Congress failed to appreciate at the time was the current state of protein characterization science and, consequently, whether interchangeability could in fact be obtained or what level of biosimilarity was acceptable.

	The major differences between small therapeutic molecules that are subject to the DPCPRA and biological therapeutic molecules that are the subject of the BPCIA are detailed in Table 1.

	As has been well documented in the years prior and subsequent to the passing of the BPCIA, the analogy of “generic” does not transfer well from the realm of small-molecule drugs to that of biologics, due primarily to biologics’ considerably larger molecular size and complexity of manufacturing that may affect the final product in terms of tertiary structure or post-translational modifications.

 The Food and Drug Administration (FDA) recently finalized three guidance documents to help clarify expectations regarding the concept of “biosimilarity” and thereby to assist manufacturers in the development and approval of biosimilars.

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

Q&As Regarding Implementation of the BPCI Act of 2009

“Guidance for Industry: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants”

	Despite the earlier availability of the guidances in draft version, no biosimilars were approved by the FDA until this year. In March, the agency approved the first-ever biosimilar therapy in the U.S., clearing Zarxio  (filgrastim-sndz), a biosimilar to Amgen’s Neupogen (filgrastim), which is used to increase white blood cell counts in cancer and bone marrow transplant patients. Sandoz, a unit of Novartis, is the maker of Zarxio. 

	While more approvals are likely to follow, as the initial dearth of activity illustrated, biosimilar developers in the U.S. will remain challenged to advance their products to market. The primary reason is that the additional work required to demonstrate similarity of the efficacy and safety of the biosimilar molecule to the original approved biologic is sufficiently burdensome to make approval via the original approval pathway for biologics (351(a)) equally attractive to biosimilar manufacturers.  Also, by choosing the 351(a) biologics license application (BLA) innovator biologic pathway, the company is entitled to a 12-year marketing exclusivity period associated with this development pathway versus as little as 12 months of marketing exclusivity if it was approved as a biosimilar (351(a)(6)).

	The FDA espouses that clinical and nonclinical work will be abbreviated for biosimilar approval and that approval will be granted on the basis of the “body of evidence” provided by the manufacturer, but that each application will have to be handled on a case-by-case basis. However, this is potentially much more labor intensive than the traditional biologic development process familiar to pharmaceutical and biotechnology companies. Development of a biosimilar currently requires significant comparability work be agreed upon a priori with FDA and this work must be “front-loaded” in the development program. Depending upon the results of this comparability nonclinical and manufacturing work, additional work most likely will be required.

	The FDA recently released another guidance relating to its evolving standards for satisfying the biosimilarity requirements of the Biologics Price Competition and Innovation Act (BPCIA) that focused on clinical pharmacology study requirements: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product.6

	This guidance details the recommendations for the design and conduct of pharmacokinetic and pharmacodynamic studies, which will provide data for only one element in the eventual evaluation by FDA of the biosimililarity of a newly submitted biosimilar product to the approved reference product. In addition to the clinical pharmacology study or studies needed for an approval of a biosimilar product, additional clinical studies may be required along with the requisite bioanalytical molecular comparisons between the biosimilar and the reference product.

	There are several companies that have successfully gained marketing approval for biosimilars in Europe who have assisting FDA in determining the data package required for approval of a biosimilar in the U.S. The difficulties stem to some degree from the division of the FDA into the Center for Biologics Evaluation and Research (CBER) and the Center for Drugs Evaluation and Research (CDER) due to evolutionary organizational reasons. The European Medicines Agency (EMA) is able to bring to bear the same scientists to evaluate small molecules and biologics and, as a result, there is not the same degree of separation of opinions about how each type of molecule is regulated within one agency. Consequently, the EMA was able to foresee this biosimilar pathway’s emergence much earlier and issue a number of class specific guidances that contain specific recommendations for development.

	Also, achieving an FDA determination of true interchangeability of a biosimilar versus an original biologic product as exists for generic and innovator small-molecule drugs will not be accomplished until a great deal more is understood about the biochemical processes generating these molecules and the contributions of the various regions of the molecules to efficacy and safety concerns. Of primary concern is the contribution of the various structural elements of the biosimilar molecule to the safety concerns in clinical studies. Efficacy can more easily be demonstrated in a reasonably sized clinical development program, but it is safety that regulators struggle to define the minimum number of subjects that represent a sufficient safety data base to warrant marketing approval.

	The scientific methods that are used to determine molecular similarity are currently insufficient to specifically identify the relationship between differences between a biosimilar and an original biologic. For example, assigning an adverse event observed in a clinical study to a specific peak in a mass spectrometry profile is imprecise at best, but we are nowhere near this level of precision at the current time. Consequently, the regulatory authorities emphasize that the “body of evidence” will determine their judgment as to the biosimilarity of a molecule. The FDA has championed the need to consider the safety of pharmaceuticals and biotechnology products as a science, but the integrated effort required to produce these types of results has been slowly embraced by industry, academia, and governmental agencies. Until much more work is done defining the relationship between structural elements of a biological molecule and the adverse events observed in the clinic, the determination of biosimilarity with regard to safety remains largely subjective.

	Consequently, while many large pharma companies have announced their intention to develop biosimilars, many manufacturers have chosen to develop alternative products designed to be more than just biosimilar-biosuperiors or biobetters.

 These are products similar to the original approved biologics, but with some measurable superiority such as extended therapeutic effect time or a reduced adverse event profile. These products are being developed and approved via the traditional 301(a) BLA pathway for biologics and are required to demonstrate efficacy and safety without the necessity of comparability studies designed to demonstrate their similarity to the originator molecule.

	This approach has several advantages. First, it relieves the product sponsor from conducting a large Phase III active-control clinical study versus the innovator biologic demonstrating equivalence. These types of studies are larger and less scientifically rigorous than clinical studies versus placebo, and carry all the vagaries of generating meaningful data from a clinical study.3  Of course, the efficacy of the biosuperior product has to generate efficacy and safety data demonstrating a benefit/risk ratio of the same approximate magnitude as the innovator product, but not in a head-to-head comparison. The biosuperior developer will be measured against the results obtained by the innovator in their current package insert. Consequently, the work required for approval of a biosuperior would more closely resemble the 505(b)(2) new drug approval (NDA) regulatory pathway for “improved” approved drugs leveraging FDA’s knowledge of previously approved innovator products as opposed to the 505(j) NDA pathway for generic drugs with its expectations of interchangeability.

	In fact, the 505(b)(2) pathway has already been utilized in the approval of biosimilar molecules that fall under the purview of the CDER as opposed to those which fall under the CBER. For historical reasons, hormones are regulated by the Food Drug and Cosmetics Act of 1938 and not the PHS Act. Consequently, well-characterized hormone molecules such as insulin and somatropin have several products competing for the market and undoubtedly put pressure on the original innovator price of these products. In Europe, where there is no distinction between the approval pathways for drugs and biologics, several molecule-specific guidances have been issued to assist product sponsors with the development of these well-characterized molecules (i.e., insulin, somatropin, erythropoietin, granulocyte-stimulating hormone, follicle-stimulating hormone, and interferon).

	One might argue that focusing on biosuperiors defeats the original purpose of legislation for development of biosimilar products, i.e., the reduced sales cost to the consumer that has been well documented in the generic drug market. However, due to the complexity of development of biologics, the expected sales price of biosimilars was anticipated to originally be in the range of 70% to 80% of the originator molecule as opposed to the about 30% of the originator drug that has been documented for generic drugs.

 Consequently, the price competition that might result from the presence of viable biosimilars on the market was never expected to be game-changing for consumers the way that small-molecule generics have been. For biosuperiors, the degree of superiority represented by the biosuperior competitor may alter this dynamic significantly, perhaps leading to a premium price for the biosuperior relative to the innovator product. In general, it is safe to assume biosimilars and biosuperiors will not realize anywhere near the degree of price discount seen with small-molecule generics.

	Aside from questions around how to prove “biosimilarity” or the likely effects on product pricing, the current debate raging between the companies manufacturing biosimilars and innovators revolves around the International Nonproprietary Names (INN) convention for biosimilars.

  The companies manufacturing biosimilars, reasoning along the same lines as the intent of Hatch-Waxman for generic drugs, argue that all derivatives of an innovator molecule must possess the same INN name. However, the manufacturers of the innovator molecules argue that while similar, the subsequently approved biosimilar molecules will likely possess significant differences in glycosylation and tertiary structure and, consequently, should be examined separately for adverse events that may not be affiliated with the safety profile of their innovator molecules. With a bona fide biosimilar approved now in the U.S., this discussion around regulatory protein science should continue to advance and hopefully evolve to the point where detailed molecular structural information can definitively be matched with the safety and efficacy events a biological product demonstrates. 

	Was it possible to see the evolution of biosimilars and biosuperiors prior to the passage of the BPCIA? Much of the prior debate focused on whether it was even possible to manufacture a biosimilar to the exacting standards required to mimic the efficacy and safety of an approved biologic. Large pharma emphasized the inability of biosimilar manufacturers to replicate the complex structure of biologics and, hence, predicted the introduction of unknown safety concerns attributed to the changes in structure. Nonetheless, many large pharma companies stated their intent to refocus some of their efforts on biosimilars while others steadfastly avoided this commitment or expressed their intent to pursue biosuperiors. The development of biosuperiors will no doubt also encounter some regulatory hurdles not experienced during the development of innovator molecules. For one, it will be of critical importance for the developers of biosuperiors to convincingly demonstrate to FDA their advantage over the innovator molecule if they intend to advertise that distinction. Hence, the current state of protein science seems to augur approval decisions and court battles focused on the clinical relevance of the superiority rather than the similarity of biosimilar compounds to innovator molecules.

	1. Prugnaud, J-L., and J-H. Truvin, eds. “Biosimilars:  A New Generation of Biologics.“ Springer-Verlag France, Paris, 2011.

	2. Armstrong, W. “MedImmune Bets Its Fate on ‘Biobetters’.” 2011; PharmExecBlog. 

	3. International Conference on Harmonisation of Technical Requirements For Registration of Pharmaceutical For Human Use. Structure and Content of Clinical Study Reports. E3. 1995. Section 9.2 p 6.

	4. Use of Generic Prescription Drugs and Brand-Name Discounts. National Conference of State Legislatures Briefs for State Legislatures. In Health Cost Containment and Efficiencies. 2010; No. 8.

	5. Karlin, Sarah.  “Naming Rights: Biosimilar Influence Efforts Continue Before Products Take the Field.” The Pink Sheet, 2013; Vol 75. No. 43. p 5 – 7.

	6. Pollock, B.  “What’s in a Name? GPhA Says, Everything – for Biosimilars.”  2013; Lachman Consultants Blog. 

A regulatory perspective on the current state of protein science and the implications for biosimilar approval.

David Shoemaker, PhD

Articles

The Gene Therapy Product Development Process

The U.S. Biosimilar Pathway: Policy Precedes Science