FDA Today | When is a Gene Therapy the ‘Same’ as Another Therapy? FDA Explains.

The FDA published a lot of guidance documents this week. We managed to analyze almost all of them already, and today we want to walk you through one of the more complex documents on gene therapy “sameness.” It’s a really interesting topic, but it requires quite a lot of context to understand.

So get cozy, because we have a full analysis on the topic for you below. AgencyIQ subscribers can also read about the other gene therapy guidance document that came out yesterday on how sponsors can study multiple versions of gene therapies here.

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When is a gene therapy the ‘same’ as another? Final FDA guidance explains what it means for orphan drug benefits

The top line: The FDA has published a final version of a guidance document explaining when a gene therapy product is the “same” as another product – a critical determination for unlocking special incentives for product developers, including tax incentives, marketing exclusivity and other savings. While the guidance is largely the same as the draft version first published in January 2020, it does provide some additional clarity requested by members of the biopharmaceutical industry.

First, let’s provide some regulatory background. Fair warning, this is a complex topic.

• In order to incent the development of treatments for conditions that affect a small patient population, Congress passed the Orphan Drug Act (ODA) in 1983. That law created the Orphan Drug Designation and its associated incentives. Orphan drugs are those intended to treat “rare” diseases, which are defined in the ODA as conditions impacting fewer than 200,000 individuals in the US or fewer than 200,000 member of a distinct subpopulations, among other considerations.
• To qualify as an orphan product and be considered for regulatory incentives, products must meet certain regulatory criteria to be considered. Critically, the product must both meet the “rare” disease requirement in statute and not be the “same” as another available treatment. This is meant to prevent follow-on products (such as generics) from obtaining lengthy periods of marketing exclusivity, for example. It’s also meant to avoid companies from accessing valuable incentives (more on that below).
• The FDA defines “sameness” for drugs based on their composition and their intended use. For example, for small molecule drugs, sameness means drugs that have the same active moiety and are intended for the same use, while for larger-molecule drugs, it refers to drugs of the “same principal molecular structure” that are intended for the same use. An exception to the sameness criteria, though, is if a new proposed product is “shown to be clinically superior” to an already approved product that is similar in composition and intended for the same use. Very few of these superiority considerations have been granted, however.
• If the FDA’s Office of Orphan Drug Products (OOPD) grants the orphan drug designation, the product sponsor is granted three key benefits: Tax credits worth 25% of the qualified costs of product development; an exemption from certain prescription drug user fees for new applications; and the potential for seven years of market exclusivity if the product is approved. However, for biological products, for which 12 years of marketing exclusivity is given to products for new indications, this latter incentive is generally not as important.

Ok, with that background out of the way, let’s start exploring the heart of the issue: When are two products “the same” for regulatory purposes?

• For some drugs, such as small-molecule products, it can be somewhat obvious when two drugs are the “same.” If the drugs contain “the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug,” then it’s the same – even if there are differences in the ester or salt – unless the subsequent product is clinically superior.
• But things get far more complex once you start dealing with biological products, which have far greater inherent differences. The FDA’s existing regulations do indicate that it applies the “sameness” threshold differently to “protein drugs” than it does to either small molecules or macromolecules.
• For protein-based products, the FDA’s “sameness” regulations explain that two products “would be considered the same if the only differences in structure between them were due to post-translational events or infidelity of translation or transcription or [there] were minor differences in amino acid sequence.” Even some “potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the differences were shown to be clinically superior.”
• This approach applies to other complex products as well, including polysaccharide drugs (“considered the same if they had identical saccharide repeating units, even if the number of units were to vary and even if there were postpolymerization modifications”), and polynucleotide drugs (“considered the same if they had an identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone”). It also applies to what the FDA calls “closely related, complex partly definable drugs with similar therapeutic intent,” such as two live viral vaccines for the same indication.
• However, there is currently no established regulatory definition from the FDA defining how the agency will apply the sameness criterion for gene therapies. In fact, the FDA doesn’t even have a regulatory definition of the term “gene therapy,” either. According to agency guidance, FDA considers human gene therapies to include products intended to “modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use.” This includes all products “that mediate their effects by transcription or translation of transferred genetic material, or by specifically altering host (human) genetic sequences.”
• As with other biological products, the basic idea of “sameness” for gene therapy products is highly complex. For example, genetic modification may occur inside of the body, such as through the injection of genetically-modified material, or outside of the body, such as through genetically modifying cells removed from the body. Modification may take place using modified versions of a patient’s own cells, or modified versions of cells not from the patient. Modification may also take place using a wide variety of different “vectors,” through which the genetic material is transferred into a patient’s cells. These vectors typically involve inactivated viruses, such as lentiviruses, adenoviruses, various retroviruses and even herpesviruses.
• For the FDA, these therapies pose a novel question: When is a gene therapy the “same” as another therapy? For example, if the therapy uses the same vector (e.g., the same adenovirus vector) as another therapy, would that cause it to be the same? If it used the same modified cells not taken from the same patient, could that be considered the same? Or are those merely vehicles, and the real difference comes down to the genetic modifications (i.e., transgenes) themselves?
• The answer to this question is important for gene therapy developers. In practical terms, it’s the difference between being eligible for the 25% tax credit and saving the PDUFA application filing fee. As of FY 2022, the fee to file a Biologics License Application requiring clinical data is $3,117,218 – a powerful incentive for companies to demonstrate their differences.

The FDA first tried to answer this question last year with a draft guidance. Let’s talk about what that guidance document said.

• The FDA provided a preliminary answer to this question in January 2020 when it released its draft guidance document, Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations. As explained in the document, the “FDA generally intends to consider certain key features such as transgenes and vectors used in gene therapy products to be ‘principal molecular structural features’ under this regulation.”
• Critically, the FDA said that transgene differentiation will typically be sufficient to demonstrate that products are not the “same.” According to the FDA, “If two gene therapy products express different transgenes … and have or use different vectors, FDA generally intends to consider them to be different drugs for purposes of 21 CFR 316.3(b)(14)(ii) because they will not contain the same principal molecular structural features.” This would apply even if the transgenes were expressed using the same vector.
• Conversely, companies could also use different vectors to administer the same transgenes and the FDA would still consider them “to be different drugs … because they will not contain the same principal molecular structural features.” However, the vectors used will have to be from “a different viral class,” the FDA noted. In instances in which vectors from the same viral class are used (e.g., AAV2 vs. AAV5), the FDA will make a determination regarding sameness “on a case-by-case basis.”
• Finally, the FDA said that it would also consider “additional features,” such as regulatory elements and the cell type that is transduced,” when making a determination. That could help products that express the same transgene and use the same vector for administration. In these cases, the FDA said it will consider the extent to which those additional features “contribute to the therapeutic effect” of the gene therapy product. While the agency didn’t provide much in the way of clarity about its intended evaluation process here, it did say that its litmus test will be whether the features constitute “principal molecular structural features.”
• More than a dozen companies wound up submitting comments to the FDA about its sameness guidance, and the FDA even extended the comment period in April 2020 following requests for additional time. For example, the American Society of Gene & Cell Therapy (ASCGT) requested that the FDA provide more information regarding when sponsors should ask about sameness during development in order to get insight as early as possible. Many companies, including ASGCT and bluebird bio, asked for additional examples and to clarify the “additional features” referenced above. Most companies asked for clarification regarding specific definitions. For example, the industry group BIO asked how gene editing approaches might be regulated, and Regeneron asked for clarification about how the FDA defines “minor differences” discussed in the guidance. [ For more information, please see AgencyIQ’s comment analysis.]

Now the FDA is out with a final guidance document. Let’s talk about what it says, what changed relative to the 2020 draft guidance, and what it might mean in practical terms.

• Today, the FDA issued its final guidance on the sameness guidance, offering responses to some industry concerns. In general, however, the substance of the guidance is little changed relative to the January 2020 draft.
• Notably, the final guidance offers a bit more detail regarding how the FDA will assess the “sameness” of gene therapy vectors. Previously, the agency wrote that “if two gene therapy products have or use vectors from a different viral class,” it will treat them as different drugs. In the updated version, the FDA now only states that it will treat them as different if they “have or use different vectors.” No mention is made of a “different viral class” in the base explanation. Instead, the FDA has added two examples which explain that it considers “different vectors” to include vectors from a “different viral group” to be different, and vectors from the same viral group to be different “when the differences between the vectors impact factors such as tropism, immune response avoidance, or partial insertional mutagenesis.”
• There are some additional examples included throughout the document as well. For example, FDA includes polymorphism as an example of a “minor difference” that would not affect a finding of sameness. FDA also notes that it will consider such differences on a case-by-case basis. In another example, the FDA adds examples of the “additional features” that could raise to the level of a significant differences including “promoters, enhancers, or splicing elements.”
• A few thoughts on this guidance from AgencyIQ. At multiple points throughout the guidance, the FDA notes that it will consider the sameness of products on a case-by-case basis. Expect that guidance to result in many requests for early-stage meetings with the FDA and OOPD. The FDA may wish to maintain a list of such requests and responses to ensure consistency and cut down on the number of requests it receives, similar to how it maintains guidance on popular questions asked during the drug development process. Since nearly all gene therapies are for rare diseases, encouraging more interactions with the agency could strain existing resources, especially as the field continues to expand.
• Another thought: Without formal regulation, we may see challenges to these determinations in court. The value of an orphan drug exclusivity period can be worth quite a lot, and companies have not been shy about trying to protect that exclusivity. As the FDA notes in the guidance document, guidance isn’t legally binding, meaning that companies should be prepared for challenges at both White Oak and in the court system for this one.

What we're watching and reading

• …this report in the Associated Press which found that during a period of FDA enforcement discretion, hundreds of clinics began selling unapproved stem cell treatments for various conditions – hundreds more than when the enforcement period began. The article indicates that the number of stem cell clinics that have made an effort to register with the FDA is “troubling low.” AgencyIQ subscribers can read more about this issue here.
• …this analysis indicating that some companies are self-certifying dietary supplements as “GRAS” – Generally Regarded as Safe – to get around FDA regulatory safeguards meant to enhance scrutiny of New Dietary Ingredients (NDIs).
• …this HHS plan on contingencies in case the government does shut down this week in the absence of a budget. (And also this nice explanation by Bloomberg’s Jeannie Baumann and Ian Lopez on some other aspects of the shutdown you should be thinking about in case it happens.)
• …this report from our POLITICO colleagues that Democrats appear to be dialing back their drug pricing plans in a bid to win over moderate legislators.
• …this report about CBER Director Peter Marks' views about what to call the third dose of Covid-19 vaccine. Is it a booster, or is it the “third dose of a primary series”?
• …this wave of new contract notices being sent out by the FDA (it is the end of the fiscal year, after all). There’s the $1.1 million for a “maturity assessment in support of the FDA’s Sentinel System.” The $7.6 million to support the CDRH’s Case for Quality initiative. The $1.2 million to support FDA’s BEST initiative, which conducts surveillance of biologics. The $350,000 to support oncology patient-focused drug development. $750,000 to support the validation of a novel method of assessing the response to Lymphoma treatments in real-world studies. And $36 million to support the FDA’s Office of Regulatory Affairs, including investigations, imports and systems for inspections, recalls compliance and enforcement.
• …this updated list of transcripts from the FDA’s diagnostics “Town Hall” meetings. Transcripts are now current as of late August. (AgencyIQ covers those meetings and has same-day analysis).
• …this report by the Congressional Research Service about the approval of Pfizer’s Comirnaty vaccine.
• …this hiring notice for a senior advisor for the FDA’s Office of Vaccines Research and Review.
• …this legislation which calls for HHS to “establish a new program which ensures meaningful access to claims data by clinician-led clinical data registries.” That could benefit companies looking to make use of real-world data.
• …this legislation which would allow for the re-review of certain patents by the Patent and Trademark Office to ensure they are “high-quality.”
• …this research by 11 FDA staffers on opioid abuse and labeling. “Our assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs.”
• …this safety communication about potential injuries associated with the Safe-T-Lite UV Wand, a germicidal wand used to help disinfect surfaces, which the FDA says could expose both the user and an nearby persons to “unsafe levels of UV-C radiation and may cause injury to the skin, eyes, or both” after just a few seconds of use.

Analysis available exclusively to AgencyIQ subscribers:

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The FDA today heard input from industry leaders and public stakeholders about their perspectives on the recently released PDUFA VII commitments. Overall, industry expressed strong support for key programs and efforts, with the only real concern that FDA isn’t prepared to move quickly enough to implement some programs and initiatives.

European Commission opens consultation on planned revisions to pharmaceutical legislation

Today the European Commission opened a public consultation on issues relating to the planned revision of the Pharmaceutical Legislation. The revisions aim to build a “future-proof and crisis-resilient regulatory framework” that simultaneously supports pharmaceutical innovation and access to medicines for E.U. citizens.