The twenty-two regulatory pathways the FDA is likely to leverage to get new COVID-19 therapies to patients

The FDA has more than 50 regulatory pathways available to companies hoping to get a new drug or biologic approved. Here are the 22 that are most likely to be used to help bring new COVID-19 products to patients.

 

Alexander Gaffney is the author of this piece (agaffney@agencyiq.com)

 

 

The life sciences industry is already hard at work developing potential treatments, cures and vaccines for COVID-19. While most of these therapies are still more than a year away from completing clinical testing, many companies are already considering the regulatory through which they could seek FDA approval. 

 

 

By AgencyIQ’s count, there are more than 50 ways for a drug or biological product to obtain approval or market access in the US. But for COVID-19, 22 of those pathways to market are likely to be used to help market new products.

 

In this analysis, AgencyIQ will explain what those pathways are, how they typically work, and why they might be useful to companies hoping to develop products for COVID-19.

Which regulatory pathways will companies make use of to bring COVID therapies to market?

 

Pathways specific to COVID-19

Coronavirus Treatment Acceleration Program

  • What it is: A “special emergency program” intended to accelerate the review of therapies intended to treat, cure or prevent COVID-19. The review program “uses every available method to move new treatments to patients as quickly as possible.” The pathway combines many elements from other review programs and pathways listed below, such as rolling review, accelerated timelines, hands-on support from FDA review staff and more.
  • The pathway is intended to begin early in clinical development, with the FDA providing “ultra-rapid, interactive input on most development plans,” review of clinical protocols within 24 hours of submission, review of single patient expanded access requests “generally within 3 hours” and working collaboratively to conduct quality assessments and transfer manufacturing “to avoid supply disruption.”
  • What it’s generally used for: The acceleration of medical therapies intended to treat, cure or prevent COVID-19.
  • Limitations: As with other review acceleration methods, the FDA’s ultra-rapid review will only be as useful as the ability of a company to move quickly to establish a manufacturing site, generate and analyze data, and make submissions. The ultra-rapid reviews may also miss some critical safety or efficacy issues that might have been discovered through more extensive analysis.
  • How it could be used in the context of COVID-19: Expect all COVID-19 products to receive an all-hands review by the FDA, with some product reviews taking place in days instead of months. The FDA says it plans to “continue to enhance and expand CTAP,” so further changes are expected soon.
  • Further reading: Coronavirus Treatment Acceleration Program
  • Also known as: CTAP
  • Regulatory/Legal authority: N/A. More akin to a pilot program, and not established under regulation or statute.

 

 

Pre-approval pathways

Expanded Access

  • What it is: Under federal regulations, the FDA can allow companies to make investigational drugs available to patients on a compassionate basis. Access to these investigational products is typically limited to patients with a serious or immediately life-threatening disease or condition for which there is no FDA-approved treatment. There are several types of expanded access authorities, including for individuals, small groups of patients, and large groups of patients (such as an entire population). Access may be granted on either a standard basis or emergency basis, depending on the health of the patient(s).
  • Critically, companies may charge money for access to an investigational drug under expanded access, though they are limited in how much they can charge. Products under this pathway are not approved, but in some cases may be available to patients in sizable quantities. Sponsors must submit either an IND Protocol or a Protocol Amendment.
  • What it’s generally used for: Providing access to investigational drugs for very sick patients who otherwise wouldn’t qualify for a clinical trial. Expanded access is most often used for patients with cancer or infectious diseases.
  • Limitations: While the FDA approves 99% of all Expanded Access requests, the pathway may be difficult for pharmaceutical companies to participate in, as they may not have enough manufacturing capacity to ensure the supply of a drug to both their existing clinical trials and patients seeking to access a drug on a compassionate use basis. In addition, a company also may not be able to recoup all costs of participating in Expanded Access, since there are legal restrictions on what they can include in the cost.
  • How it could be used in the context of COVID-19: Because Expanded Access permits large numbers of patients to access a drug before it is approved, the FDA has already begun to permit some companies to make their investigational drugs available to COVID-19 patients. However, access is no guarantee of benefit, and patients may be exposed to significant risks. Companies are likely to be under substantial pressure to permit access to their experimental drugs and may find it difficult to withstand that pressure.
  • Further reading: FDA Public Health Focus: Expanded Access
  • Also known as: “Compassionate Use
  • Regulatory/Legal authority: 21 CFR 312.305

 

Right to Try

  • What it is: The Right to Try (RTT) pathway permits a drug company to make an investigational product available to a patient with a life-threatening disease or condition who has exhausted approved treatment options and is otherwise ineligible for a clinical trial for the drug. To qualify, the investigational product must have completed a Phase 1 clinical trial.
  • While the pathway is conceptually similar to Expanded Access, there are a few key differences. RTT offers a legal liability shield for participating companies, includes no requirement for the company to obtain review by an Institutional Review Board, allows companies to charge for access to the drug, and places restrictions on the FDA referencing adverse events uncovered during the use of the RTT product during a subsequent review for the purpose of approval.
  • What it’s generally used for: Providing access to investigational drugs for very sick patients who otherwise wouldn’t qualify for a clinical trial. Right to Try is most often used for patients with cancer, neuromuscular conditions or infectious diseases, but large pharmaceutical companies rarely use the pathway.
  • Limitations: The RTT pathway requires companies to willingly participate and provide access to their products. However, there are several factors that could limit company willingness, including internal company policy, the condition for which treatment is sought, or their manufacturing capacity for the drug. As critics of RTT have noted: It’s more akin to a “Right to Ask” than a “Right to Try.” To date, very few people have obtained access to pharmaceutical products through this pathway.
  • How it could be used in the context of COVID-19: Right to Try offers a low bar for access to an experimental therapy. Because the pathway operates largely outside the scope of the FDA’s jurisdiction, some companies may seek to use it to bring products to COVID-19 patients more quickly. However, the pathway may also be leveraged as an opening for unscrupulous activity on the market, including by those hoping to profit from making investigational products available to patients.
  • Further reading: FDA Learn About Expanded Access and Other Treatment Options: Right to Try
  • Also known as: The Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017
  • Regulatory/Legal authority: 21 USC 360bbb-0

 

 

Emergency and Case-by-Case Methods

Emergency Use Authorization

  • What it is: If a public health emergency is declared by HHS, and a subsequent declaration is made that the public health emergency justifies market access of unapproved medical products, the FDA may authorize the emergency use of specific products under specific conditions. This process, known as Emergency Use Authorization (EUA), allows marketing of a product if the FDA determines that a product “may be effective” in diagnosing, treating or preventing a disease, condition or agent identified in the emergency declaration, and that the benefits of the product outweigh its risks. This differs significantly from the ordinary standard for FDA approval, which requires “substantial evidence” that a product is effective andsafe for use. Additionally, for a product to receive and EUA there must not be any “adequate” approved treatment available on the market.
  • This pathway allows the FDA to waive significant portions of federal regulations, including requirements to manufacture a product according to current good manufacturing practices. Under this pathway, products are not technically approved. Instead, products with an EUA are “authorized” for use for a set period of time, subject to reauthorization, after which it may be removed from the market. Federal law also permits government stakeholders to stockpile or “forward-deploy” the medical product before it is authorized, in anticipation of it obtaining that authorization.
  • What it’s generally used for: Authorizing the use of drugs, biologics and diagnostics for dangerous pathogens like Ebola and influenza, as well as medical countermeasures for chemical, biological, radiological or nuclear events.
  • Limitations: EUAs typically are not authorized with significant clinical data or assurances as to their safety or efficacy, and it can be difficult to convert an EUA to a full approval, as use of a product under an EUA doesn’t lend itself to collecting the type of clinical evidence needed to support full approval. Very few drugs or biological products qualify for this authorization pathway, though it is used extensively for medical devices and diagnostics, which generally present less risk to a patient. A sponsor is under no obligation to sell the product authorized for use, and the FDA is not able to compel them to do so.
  • How it could be used in the context of COVID-19: The FDA may ultimately leverage the EUA pathway heavily to make products available to the public for COVID-19. Already, it has issued an EUAfor the Biomedical Advanced Research and Development Authority (BARDA) to use supplies of chloroquine phosphate and hydroxychloroquine sulfate that were donated to the national stockpile as a treatment for COVID-19. Because the pathway is substantially faster than traditional approvals, while also preserving the right for regulators to remove a drug from the market later, it may be an attractive option for making available products that have not been subject to extensive review.
  • Further reading: FDA Guidance Document: Emergency Use Authorization of Medical Products and Related Authorities
  • Also known as: EUA
  • Regulatory/Legal authority: 21 USC 360bbb-3

 

Enforcement Discretion

  • What it is: Under precedent set by the Supreme Court (Heckler v. Chaney), regulatory agencies like the FDA have the broad authority to determine when and how to use their regulatory authority (subject to some limitations and judicial review). In rare cases, this allows the agency to selectively permit companies to break its regulatory processes in situations where the agency determines that doing so would be a public good or otherwise necessary.
  • What it’s generally used for: Enforcement discretion is generally used in cases of emergency, cases of public importance, to deal with drug shortages, to provision of death penalty drugs, or to provide carve-outs of FDA’s existing authority where the agency may not wish to relinquish its authority to regulate in the future.
  • Limitations: Companies and public advocacy groups may challenge the FDA’s use of enforcement discretion in court. At various times, the FDA has lost these cases, in particular when trying to permit the importation of unapproved drugs used by some states to execute prisoners. While the FDA may choose not to make use of its authority, it does not have a blank check to ignore the will of Congress.
  • How it could be used in the context of COVID-19: The FDA has already made ample use of its enforcement discretion during the COVID-19 pandemic to loosen longstanding regulatory policies. Using that approach, it has said it will not take action against companies that, for example, make products like hand sanitizer and chloroquine that would ordinarily be in violation of federal law or make changes to already marketed respiratory equipment. In doing so, it is making more products available without first needing to obtain regulatory approval.
  • Further reading: http://www.fdalawblog.net/2019/05/holidays-and-red-herrings-fdas-nonenforcement-discretion-successfully-challenged/
  • Also known as: Nonenforcement discretion
  • Regulatory/Legal authority: Heckler v. Chaney, 470 U.S. 821 (1985)

 

Normal methods

New Drug Application

  • What it is: A New Drug Application (NDA) is the primary submission vehicle through which a company (i.e., “sponsor”) requests FDA approval of a drug. The standard of approval is based on substantial evidence that a product is safe and effective for a specific indication, and that it is manufactured to appropriate quality standards.
  • What it’s generally used for: The submission and approval of new drugs that have either never before been approved (known as new molecular entities) or new uses for drugs that have already been approved (known as indications).
  • Limitations: Filing an NDA through this pathway is expensive and time-consuming. An application requires extensive evidence to support approval, a lengthy clinical development timeline, extensive pre-clinical testing, lengthy FDA review and a regulatory filing fee of nearly $3 million. A standard application also takes 12 months to review (10 months, plus 2 months of administrative review). An NDA is not suitable for use by biological products, which must use the Biologics Licensing Application (BLA) process.
  • How it could be used in the context of COVID-19: While a drug to treat COVID-19 may first become available through Emergency Use Authorization or Expanded Access, a company likely will eventually seek full approval for the product. The NDA pathway would be the process through which that drug would eventually seek approval (unless it is a biologic).
  • Further reading: FDA Types of Applications: New Drug Application (NDA)
  • Also known as: 505(b)(1)
  • Regulatory/Legal authority: 21 CFR 314; 21 USC 355(b)(1)

 

Biologics Licensing Application

  • What it is: A BLA is one of a handful of core application processes through which the FDA reviews medical products. In particular, the BLA is used to review biological products regulated under 21 CFR 601. As with NDAs, a BLA is intended to require the submission of “substantial evidence” to support the marketing of a new application, including original pre-clinical and clinical data.
  • What it’s generally used for: Any biologic product, which includes those comprised of a virus, therapeutic serum, toxin, antitoxin, or analogous product. Therapeutic DNA plasmid products, therapeutic synthetic peptide products of 40 or fewer amino acids, monoclonal antibodies intended for in vivo use, and therapeutic recombinant DNA-derived products are also considered biologics.
  • Limitations: As with an NDA, filing a BLA is expensive and time-consuming to file. An application requires extensive evidence to support approval, a lengthy clinical development timeline, extensive pre-clinical testing, lengthy FDA review and a regulatory filing fee of nearly $3 million. A standard application also takes 12 months to review (10 months, plus 2 months of administrative review). A BLA is not suitable for use by non-biologic products, which must use the New Drug Application (NDA) process.
  • How it could be used in the context of COVID-19: While a biologic therapy to treat COVID-19 may first become available through Emergency Use Authorization or Expanded Access, a company likely will eventually seek to have the product granted full approval. The BLA pathway would be the process through which that biologic would eventually seek approval (unless it is a small-molecule drug).
  • Further reading: FDA Development & Approval Process (CBER): Biologic License Application (BLA) Process
  • Also known as: BLA, 351(a)
  • Regulatory/Legal authority: 21 CFR 601

 

505(b)(2) Pathway

  • What it is: A 505(b)(2) application is an NDA (see above) filed by a sponsor who has not obtained the right to reference study data contained in another company’s NDA filing. In plain terms, it may reference another company’s approved drug, similar to how a generic drug might reference another approved product. However, unlike a generic drug, this drug will contain substantial differences requiring the submission of additional data in addition to the data from the original company’s application. A 505(b)(2) filing may also contain other evidence, such as published literature that was not authored by the company seeking approval.
  • What it’s generally used for: 505(b)(2) applications are most often used for the submission and approval of drugs for which a company has developed a new route of administration or another change to a drug that is no longer under patent protection from the original approval. It may also be used to approve a new chemical entity based on a review of literature (such as a drug approved for use in another market), but this is less common.
  • Limitations: The 505(b)(2) pathway does not automatically confer marketing exclusivity protections, used to limit competition for a drug without patent protection. It is also unable to be used for certain types of changes deemed by the FDA to be too minor, such as changes in the rate of active ingredient absorption (if that is the only change).
  • How it could be used in the context of COVID-19: As companies seek to quickly bring products to market, companies may determine that an already-approved drug would be a good candidate—if there were additional changes made to the product. For example, an oral tablet might be changed to be an injection meant to be easier to administer to intubated patients. The 505(b)(2) pathway could accelerate an approval decision by allowing a company to skip some testing and leverage published medical literature.
  • Further reading: FDA Guidance for Industry: Applications Covered by Section 505(b)(2)
  • Also known as: 505(b)(2); Follow-on drugs and biologics
  • Regulatory/Legal authority: 21 CFR 314.54

 

Abbreviated New Drug Application

  • What it is: An Abbreviated New Drug Application (ANDA) is the mechanism through which a company may seek approval for a generic drug product. Under an ANDA, the generic drug company must first show that their product is not in violation of any active patents. Second, it must demonstrate that its product is the same as (“bioequivalent”) to the original drug (“reference-listed product”). A company shows equivalence to the reference-listed product (RLD) by conducting studies showing the similarity of their product to the RLD. The FDA allows for some minor differences between the products under the statute that created the generic drug program, known as the Hatch-Waxman Act of 1984.
  • The FDA may also prioritize the review of some ANDAs (in 8 months instead of the standard 10) in certain circumstances, such as for drugs without adequate competition or in the case of drug shortages.
  • What it’s generally used for: The approval of all generic drugs. The pathway is especially useful for bringing low-cost entrants to market. The more generic equivalents are marketed, the greater the competition and lower the costs for American patients and taxpayers.
  • Limitations: While the ANDA pathway is substantially easier to navigate that the NDA pathway, it is still not without challenges. Chief among those challenges is the difficulty of invalidating patents that protect the RLD from competition. Such patents can hold up product approvals for years, and often cover methods of production in addition to the drug substance itself. If a patent is still valid at the time the FDA is ready to approve a product, then that product will be granted a “tentative approval” indicating that a product may not be marketed until such time as the patent (or other blocking mechanism) is declared void or expires.
  • How it could be used in the context of COVID-19: While patents and periods of marketing exclusivity are likely to cover any approved drug or biologic for a lengthy period of time (20+ years of patent exclusivity from the time of patent filing, or 5 years of marketing exclusivity if the approved drug is not under patent), a generic could ultimately help any COVID-19 treatment get into the hands of American patients on an inexpensive, ongoing basis. The ANDA pathway will also be helpful to get lower-cost copies of already-approved products to market. For example, drugs like hydroxychloroquine phosphate and chloroquine sulfate have both
  • Further reading: FDA Types of Applications: Abbreviated New Drug Applications
  • Also known as: 505(j)
  • Regulatory/Legal authority: 21 CFR 314, Subpart C

 

Authorized Generic/Authorized Biosimilar

  • What it is: An authorized generic (or biosimilar) is a drug that is marketed with the expressed permission of the drug’s (or biologic’s) original sponsor. The product is generally marketed using the drug’s “generic” name instead of its “brand” name. The drug may be marketed by another company given permission by the original manufacturer or by the original manufacturer itself.
  • However, the FDA does not consider the drug to be “generic” or “biosimilar” since it is: (1) marketed under the original company’s NDA/BLA, (2) has no discernable differences, and (3) is generally made at the same facilities. The only difference between an originator product and its authorized generic or biosimilar is the trade dress (i.e., packaging) and, generally, the price of the product.
  • What it’s generally used for: Authorized generics (or biosimilars) are generally intended to disrupt attempts by a generic drug company to obtain market share when an originator drug loses patent protection. For example, an authorized version of a product may be used by a company to offer a product for sale at a lower price point, since the authorized generic/biosimilar may not be covered by existing contracts with wholesalers or pharmacy benefit managers.
  • Limitations: Authorized generics may not be relevant in the market for a long period of time, depending on the drug for which an authorized generic is brought to market. Additional generic entrants into the market may make offering an authorized generic financially unsustainable for the original company. Even if an authorized version is available on the broader market, it may not be widely available or prescribed.
  • Previously, companies have used authorized generics of their own products to lower their rebate liability under the Medicaid Drug Rebate Program (MDRP)—a federal program intended to help contain drug costs for the program—by pooling their originator and authorized generic prices in reporting. However, Congress recently closed this loophole under the Continuing Appropriations Act, 2020, and Health Extenders Act of 2020.
  • How it could be used in the context of COVID-19: As companies rush to bring new chemical and biological treatments to market, authorized generics may inhabit a different role: A way for companies to share an NDA with other companies to ensure that massive amounts of a product are legally available in a short amount of time. Under this scenario, a company could authorize other companies to work under its NDA to market and market generic-like equivalents of a product. That would allow the original company to maintain control of its product and exclusivity long-term, while also permitting a short-term surge in manufacturing capacity and availability.
  • Further reading: FDA Abbreviated New Drug Application (ANDA): FDA List of Authorized Generic Drugs
  • Also known as: Authorized generic; Authorized biosimilar
  • Regulatory/Legal authority: 21 CFR 314; 21 CFR 601

 

Human Blood and Blood Products

  • What it is: The FDA regulates blood and blood products, primarily with the intent of ensuring that the blood supply is kept free from infectious diseases. As with Human Cells, Tissues and Cellular Tissue-Based Products, the FDA’s regulatory approach for blood products is focused primarily on the facilities in which blood donation takes place, as well as the handling of the product, eligibility and screening of donors, infection control measures and meeting additional requirements related to specific events (like the outbreak of a new disease).
  • What it’s generally used for: Whole blood products, as well as blood component products (e.g., convalescent plasma).
  • Limitations: The FDA’s risk tolerance for infectious disease in the blood supply is extremely low, which has prevented some historically marginalized groups from donating blood.
  • How it could be used in the context of COVID-19: The FDA has already issued policies to promote the use and study of convalescent plasma obtained from patients who have recovered from COVID-19 and whose bodies express sufficient quantities of antibodies. While that policy is currently conducted through the Expanded Access pathway, that product may ultimately be approved for use. If it is, it would go through review through the FDA’s Human Blood and Blood Products pathway, and may require a Biologics Licensing Application or other regulatory application.
  • Further reading: FDA Biologics Guidances: Blood Guidances
  • Also known as: Human Blood and Blood Products
  • Regulatory/Legal authority: 21 CFR 640

 

Expedited measures

Priority Review Designation

  • What it is: A review acceleration mechanism intended to allow an application for approval to be reviewed more quickly than traditional reviews (generally 6 months instead of the typical 10 months). Products are eligible if they are intended to treat a serious condition and would provide a significant improvement in safety or efficacy (or is for a qualified infectious disease) and have supporting data to justify a priority review.
  • Alternatively, companies may obtain access to a priority review process by purchasing or earning a Priority Review Voucher, which are used to incentivize the development of certain types of drugs and biologics.
  • What it’s generally used for: Drugs or biologics intended for cancer, infectious diseases, rare diseases or other serious conditions with significant unmet needs. Frequently used with Fast Track Designation.
  • Limitations: While the intended timeline for products with priority review is 6 months, the FDA may find it difficult to meet that timeline for sponsors who have purchased a Priority Review Voucher for a complex product raising novel regulatory concerns.
  • How it could be used in the context of COVID-19: The general concept of a priority review designation—that high-need products get massively accelerated review dates—is likely to be one that is used early and often. Expect almost all COVID-19 products to receive Priority Review Designation status, even if the 6-month review timeline represents a worst-case scenario. Reviews are likely to take place much, much more quickly.
  • Further reading: FDA Guidance: Expedited Programs for Serious Conditions – Drugs and Biologics
  • Also known as: Priority review
  • Regulatory/Legal authority: CDER MAPP 6020.3; CBER SOPP 8401

 

Fast-Track Designation

  • What it is: A review acceleration mechanism intended to allow an application for approval to be reviewed in a more hands-on manner by the FDA using actions intended to expedite development and review. Those actions include more frequent meetings, a “rolling review,” meetings with the FDA before clinical trials commence, and other operational help to keep drug development on-track for review. Products are eligible if they are intended to treat a serious condition and would provide a significant improvement in safety or efficacy, and data demonstrate that potential. Alternatively, a designated qualified infectious disease product is automatically eligible for the designation.
  • What it’s generally used for: Drugs or biologics intended for the treatment of cancer, infectious diseases, rare diseases or other serious conditions with significant unmet needs. Frequently used with Priority Review Designation and Qualified Infectious Disease Product Designation.
  • Limitations: Additional FDA resources alone cannot rescue a drug product that is not suitable for approval. An influx of requests for Fast Track designation have also strained the ability of FDA to assist all applicants at desired levels. Accelerated review processes may result in a fast review, but a company may not benefit from a faster approval if their manufacturing operations are not ready in time for FDA review.
  • How it could be used in the context of COVID-19: Expect every single product intended to treat, cure or prevent COVID-19 to be granted Breakthrough Therapy Designation or its functional equivalent. The FDA’s concept of “rolling review” is likely to be employed heavily, with companies submitting data to the FDA as soon as it is able to be reviewed, rather than waiting for data to be ready for a complete application (like an NDA or BLA). FDA staff are also expected to heavily assist all developers of products for COVID-19.
  • Further reading: FDA Guidance: Expedited Programs for Serious Conditions – Drugs and Biologics
  • Also known as: Fast Track Designation
  • Regulatory/Legal authority: 21 USC 356

 

Breakthrough Therapy Designation

  • What it is: A review acceleration mechanism intended to facilitate the timely development and review of products deemed to have a high potential to benefit patients in a meaningful way. Benefits include a “rolling review,” guidance on efficient drug development, and increased coordination with the FDA. The designation conveys all the benefits of Fast Track Designation.
  • A medical product is eligible for a Breakthrough Therapy Designation (BTD) if it is intended to treat a serious condition, with evidence indicating the product may result in substantial improvement to a clinical significant endpoint relative to already-approved therapies.
  • What it’s generally used for: Drugs or biologics intended for the treatment of cancer, infectious diseases, rare diseases or other serious conditions with significant unmet needs. Frequently used with Priority Review Designation.
  • Limitations: Early data that a drug represents a “breakthrough” may not be substantiated through further testing, and the designation may be revoked. Accelerated review processes may result in a fast review, but a company may not benefit from a faster approval if their manufacturing operations are not ready in time for FDA review.
  • How it could be used in the context of COVID-19: Expect every single product intended to treat, cure or prevent COVID-19 to be granted Breakthrough Therapy Designation or its functional equivalent. The FDA’s concept of “rolling review” is likely to be employed heavily, with companies submitting data to the FDA as soon as it is able to be reviewed, rather than waiting for data to be ready for a complete application (like an NDA or BLA).
  • Further reading: FDA Guidance: Expedited Programs for Serious Conditions – Drugs and Biologics
  • Also known as: BTD
  • Regulatory/Legal authority: 21 USC 356

 

Accelerated Approval

  • What it is: A review pathway intended for drugs or biologics for which there is an urgent need based on its potential clinical benefit for a patient with a serious condition for which there is an unmet need. Approvals are based on surrogate outcomes, which indicate that a product is likely to result in improved outcome for patients. For example, approval for an oncology product might be based on evidence that a tumor shrank or that a patient’s cancer didn’t progress to certain symptoms, rather than a more conclusive endpoint like Overall Survival (OS).
  • What it’s generally used for: The approval of oncology drugs for which a surrogate outcome, such as progression-free survival, is likely to indicate corresponding improvements in a more conclusive endpoint like overall survival. Based on a review by AgencyIQ, between 5% and 30% of novel drug approvals leverage accelerated approval authority in any given year (2015-2019).
  • Limitations: Surrogate endpoints may not be indicative of an eventual benefit to a patient. Some cancers, for example, may be held at bay by a drug, but the drug’s toxicities (or the cancer’s response to the drug) could shorten overall survival compared to the current standard of care.
  • How it could be used in the context of COVID-19: The FDA likely will be under pressure to accelerate the approval of drugs to treat or cure COVID-19, and preliminary data may be sufficient to support an approval determination. One key barrier to this pathway’s use likely will be the rapid course that the disease takes in most patients—just weeks. Accelerated approval is most often used in oncology patients, in which the course of disease may takes months or years. The FDA may therefore be more likely to require more conclusive endpoints for COVID-19, therefore precluding the use of accelerated approval for most products. It may, however, be useful for some products treating patients with long-term complications.
  • Further reading: FDA Guidance: Expedited Programs for Serious Conditions – Drugs and Biologics
  • Also known as: Accelerated Approval
  • Regulatory/Legal authority: 21 CFR 601, Subpart E; 21 CFR 314, Subpart H

 

Real-Time Oncology Review

  • What it is: A pilot program run by the FDA’s Oncology Center of Excellence that is intended to approve new oncology products “as early as possible, while maintaining and improving review quality and balancing the review team’s workload through data and analysis standardization and early iterative engagement with the applicants.” The program considers products that are likely to demonstrate substantial improvements over available therapies, such as drugs granted Breakthrough Therapy Designation.
  • Other considerations for consideration include straightforward study designs, studies conducted (in whole or part) within the US, easy-to-interpret clinical endpoints, and no formulation changes relative to an original drug (if the product is a supplement to an already-approved product).
  • The FDA’s goal for approving products is less than 24 weeks from the time the sponsor requests inclusion in the Real Time Oncology Review (RTOR) pilot, though it may be even faster depending on a variety of factors.
  • What it’s generally used for: The extremely rapid review of oncology products. While the pilot program is primarily aimed at supplemental applications (i.e., new approved uses for already-approved drugs), there are a limited number of original NDAs and BLAs being considered through the ROTR as well.
  • Limitations: As with other acceleration methods, a rapid review is only as good as the product, the sponsor’s ability to respond to the FDA’s questions, and the sponsor’s ability to establish and qualify manufacturing operations. Approval by the FDA, or the regulator finding that the product is safe and effective, does little to benefit patients if the company is unable to manufacture the drug.
  • How it could be used in the context of COVID-19: Similar to the “rolling review” concept included in Fast Track Designation and Breakthrough Therapy Designation, RTOR is intended to target most of the FDA’s available resources into the expedited review of a product for a condition with significant unmet needs and for which a rapid approval could meaningfully benefit extremely ill patients. This model is likely to be applied to COVID-19, with the FDA working to approve any products in weeks—not months. Expect the concept of an application being “filed” to be a loose concept, as the FDA is likely to work closely with companies to review data well before an application is even submitted. A final review by the FDA may take just weeks—perhaps even days depending on the extent of pre-filing collaboration. Already, the FDA’s Coronavirus Treatment Acceleration Program bears a striking similarity to the RTOR approach.
  • Further reading: https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review-pilot-program
  • Also known as: RTOR
  • Regulatory/Legal authority: N/A (Pilot Program)

 

Orphan Drug Designation

  • What it is: A special status designation given to products for which the intended population of affected patients is smaller than 200,000 persons (or 200,000 per year) or would otherwise be unprofitable. Companies are eligible for special incentives, including a 25% research and development tax credit, waived FDA user fees, waived requirements to conduct certain pediatric studies, and seven years of marketing exclusivity. Applicants typically get special assistance from the FDA’s Office of Orphan Products Development.
  • Products may also benefit from the designation if they represent “clinical superiority” over an existing drug, even if the drug has already been approved in another form. Many products are also given Fast Track Designation, Breakthrough Therapy Designation.
  • What it’s generally used for: Drugs for rare diseases or drugs for which there is “no reasonable expectation” of making a profit.
  • Limitations: Companies must submit data to the FDA, “with authoritative references” demonstrating that they qualify for the designation, which can be difficult to prove.
  • How it could be used in the context of COVID-19: While COVID is expected to soon infect more than 200,000 persons, at least one company—Gilead Sciences—had initially sought and received orphan drug designation for their investigational drug Remdesivir. This designation was initially granted since at the time Gilead sought orphan designation status in early March 2020, the disease had not yet been diagnosed in 200,000 Americans. After public outcry, Gilead requested that the FDA rescind the designation, which the FDA did soon after. Based on current projections, this designation pathway may become inappropriate, due to the spread of COVID-19 cases in the US with more than 160,000 cases as of March 30, 2020.
  • Further reading: FDA Developing Products for Rare Diseases & Conditions: Designating an Orphan Product: Drugs and Biological Products
  • Also known as: Orphan drug designation
  • Regulatory/Legal authority: 21 CFR 316, Subpart A

 

Animal Rule Pathway

  • What it is: The Animal Rule is a development pathway established to help guide development of drugs and biologics when it would be ethically unfeasible to test a drug in humans. The pathway relies on safety testing in humans and efficacy testing in animals that are known to have a similar pathological response to the disease or condition being tested.
  • What it’s generally used for: The submission and approval of drugs for diseases or conditions which do not often occur in the human population, such as drugs intended to treat highly deadly diseases, weapons of war (like chemical, biological or nuclear weapons). The pathway is also generally used to develop medicines of last resort for emergency stockpiles.
  • Limitations: The pathway results in drugs and biologics which are not necessarily known to be effective in humans, and sponsors must conduct extensive post-approval testing and monitoring. Any drug approved via this pathway may be withdrawn if subsequent use fails to demonstrate clinical benefit to patients.
  • How it could be used in the context of COVID-19: Although the development of a vaccine for COVID-19 may eliminate the transmission of the current strain, it will not protect against new strains that could emerge. Treatments for COVID-19, or of other significantly debilitating similar conditions like SARS or MERS-CoV, could be developed via this pathway. It could allow a company to make the investments needed to get a drug cleared for use and stockpiled, ready for the next potential outbreak.
  • Further reading: FDA NDA and BLA Approvals: Animal Rule Approvals
  • Also known as: Animal rule pathway
  • Regulatory/Legal authority: 21 CFR 314, Subpart I

 

 

Products already approved

Off-Label Use/Practice of Medicine

  • What it is: Although the FDA does not regulate the practice of medicine, the line between a medical procedure and the creation of a regulated medical product begins can be extremely difficult to determine. For some products, like cellular products, the FDA bases its regulatory authority on a concept known as “minimal manipulation” – the concept that once a bodily vessel is sufficiently modified, it becomes a medical product. This could allow some medical products to be marketed as procedures, though the FDA may sue the company to enforce its authority.
  • Another key hallmark of the FDA’s Practice of Medicine restrictions are that the agency does not regulate off-label prescribing of medications. Its regulation of this practice is restricted to regulating claims about off-label uses promulgated by producer of the product. This authority, too, is somewhat legally suspect.
  • What it’s generally used for: The prescribing of products off-label by physicians. It is also used to market biological-based procedures that could be considered to be medical products under certain circumstances.
  • Limitations: For companies, there is a significant risk of incurring regulatory enforcement action and civil penalties as the result of pursuing marketing under this approach.
  • For companies found to have engaged in off-label marketing, the Department of Justice often seeks damages under the False Claims Act, under the theory that the false claims defrauded the government by causing it to pay for drugs under the Medicare or Medicaid programs.
  • How it could be used in the context of COVID-19: One a product is approved, there are very few ways that the FDA may restrict the use of a product with the exception of approving it with Risk Evaluation and Mitigation Strategies (REMS) plans with Elements to Assure Safe Use (ETASU). In general, a physician may prescribe an approved drug for any use for which they believe a patient will benefit, even if that use has not been studied. Some already-approved malaria drugs—chloroquine sulfate and hydroxychloroquine phosphate—are already being studied for their potential use against COVID-19. If the data support their effectiveness, off-label prescribing may permit the rapid expansion of its use to many patients.
  • Further reading: FDA Information Sheet: “Off Label” and Investigational Use of Marketed Drugs, Biologics, and Medical Devices
  • Also known as: Practice of Medicine; Off-label prescribing
  • Regulatory/Legal authority: 21 USC 396; 21 CFR 1271

 

Supplemental New Drug Application/Supplemental Biologics Licensing Application

  • What it is: A pathway through which a drug or biologic sponsor can submit evidence for the indication of a product to be expanded or changed based on new evidence submitted by the manufacturer.
  • What it’s generally used for: Requests by companies for the FDA to approve new indications for already-approved drugs, as well as changes to a drug’s route of administration, comparative claims, or marketing status. Also used to change a drug’s status from prescription-only to over-the-counter .
  • Limitations: A supplemental application generally requires new and expensive clinical evidence to support the expanded indication for approval, though the FDA typically has more information about the drug since it has previously been approved.
  • How it could be used in the context of COVID-19: If a product is already approved by the FDA to treat another indication, a sponsor may submit a supplemental NDA/BLA in order to seek approval for it to treat COVID-19. This approval would confer additional exclusivity for the product, during which time no other company could seek approval for a generic version of that product. However, the sponsor would need to generate original clinical data to support their filing. This is likely to be a long-term option for certain products like chloroquine sulfate that are already approved for another indication, but are likely to be used off-label extensively before any data is available to support a supplemental application for approval.
  • Further reading: FDA Manual of Policies and Procedures (CDER): NDAs/BLAs/Efficacy Supplements: Action Packages and Taking Regulatory Actions
  • Also known as: Efficacy Supplement; sNDA; sBLA
  • Regulatory/Legal authority: 21 CFR 314.3; 21 CFR 601.12

 

Non-traditional pathways

Pharmaceutical Compounding (503A)

  • What it is: Pharmaceutical compounding involves the combination, mixing or altering of chemicals and other ingredients to make a medication for an individual patient. Pharmaceutical compounding has traditionally been overseen by state boards of pharmacy rather than the FDA. Under federal law, these compounding facilities must be run and operated by a licensed pharmacist or physician, and all drugs produced by the facility must meet the standards set by the US Pharmacopoeia or National Formulary.
  • What it’s generally used for: Making custom drugs for patients with unique medical needs. For example, a compounding pharmacy might make a liquid version of a tablet drug to help a patient who has difficulty swallowing due to oral surgery.
  • Limitations: Compounders may not make a drug that is “essentially a copy” of another drug and must make a product only after receiving a prescription for an individual patient. There are also some drugs defined by the FDA that may not be compounded due to their difficulty or because they have been withdrawn from the market. The FDA generally does not regulate the facilities at which these drugs are compounded (unlike traditional drug manufacturers).
  • How it could be used in the context of COVID-19: The FDA has already indicated it will permit compounders to make “essentially copies” of FDA-approved products to help increase the supply of products intended to address or treat COVID-19, including hand sanitizer and chloroquine sulfate and hydroxychloroquine phosphate. Compounding pharmacies are likely to be leveraged to rapidly increase production of products experiencing shortages.
  • Further reading: FDA Guidance, Compliance, & Regulatory Information: Human Drug Compounding
  • Also known as: 503(A) Compounding Facility
  • Regulatory/Legal authority: 21 USC 353a

 

Pharmaceutical Compounding (503B)

  • What it is: Pharmaceutical compounding involves the combination, mixing or altering of chemicals and other ingredients to make a medication for an individual patient. Pharmaceutical compounding has traditionally been overseen by state boards of pharmacy rather than the FDA. In 2013, the Drug Quality and Security Act established a new category of pharmaceutical compounders known as “outsourcing facilities,” of 503B facilities.
  • As compared to “traditional” 503A facilities, 503B facilities may operate at a larger scale, may compound drugs in advance of receiving a valid prescription, are regulated by the FDA and must adhere to federal standards for drug quality and manufacturing.
  • What it’s generally used for: Making larger quantities of drugs for patients with unique medical needs (relative to 503A facilities). For example, a compounding pharmacy might make a liquid version of a tablet drug to help patients who have difficulty swallowing due to oral surgery.
  • Limitations: Compounders may not make a drug that is “essentially a copy” of another drug and must make a product based on the receipt of a prescription for an individual patient (though they can make it in anticipation of receiving the prescription in limited quantities). There are also some drugs defined by the FDA that may not be compounded due to their difficulty or because they have been withdrawn from the market. Unlike 503A facilities, 503B facilities are regulated by the FDA and subject to current good manufacturing practice (CGMP) requirements.
  • How it could be used in the context of COVID-19: The FDA has already indicated it will permit compounders to make “essentially copies” of FDA-approved products to help increase the supply of products intended to address or treat COVID-19, including hand sanitizer and chloroquine sulfate and hydroxychloroquine phosphate. Compounding pharmacies are likely to be leveraged to rapidly increase production of products experiencing shortages. 503B compounding facilities may be best suited to making these products at scale, since 503A compounders are generally smaller facilities located within a hospital and may not have the ability to quickly scale production for a growing number of patients.
  • Further reading: FDA Human Drug Compounding: Text of Compounding Quality Act
  • Also known as: 503(B) Compounding Facility
  • Regulatory/Legal authority: 21 USC 353b

 

Other potential pathways

We at AgencyIQ know that the drug and biologic development process is wildly complex. While we don’t have a crystal ball, we’re pretty sure the above pathways are the ones you’re most likely to see used. With that being said, we would be remiss if we didn’t mention a few other pathways that could see use under rare scenarios related to COVID-19. These are pathways that could be useful, but generally have significant limitations that are likely to preclude their use in all but the most unusual circumstances. In no particular order:

  • 351(k) Application: Used to approve biosimilar products. Unlikely to be used since biosimilar trials take extensive trials to confirm that a product is so similar to a reference biologic that it is unlikely to cause any differences in safety or efficacy.
  • Suitability petition: Used to ask the FDA for permission to approve a generic with limited changes relative to the reference-listed drug. Unlikely to be used since compounders are likely to be able to make changes to the reference drug.
  • Citizen petition: Used by a company to ask the FDA for permission to approve a drug, or to declare that an older drug that is no longer marketed was pulled from the market for reasons not related to safety or efficacy (thereby allowing a generic version to be marketed). Unlikely to be used since petitions are generally complex and time-consuming for the FDA to review.
  • Over-the-counter monograph: Used to allow many drugs to be marketed without a prescription based on their adherence to a published monograph. Unlikely to be used since the monograph process is lengthy and requires extensive rule-making. (The recently-passed CARES Act contains measures to reform this process, but it will take time to implement).

Did we miss a pathway that you think will probably get use under a COVID-19 situation? Did you finish reading this and think that the only problem with this overview was that it wasn’t an additional 7,000 words? I would love to hear from you. Drop me a note at agaffney@agencyiq.com.

 

Additional research contributions to this piece were made by Lily Rosenfield, Aaron Badida and Laura DiAngelo.

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