US Approved Gene Therapies and Summary Basis for Approvals

The FDA presentation by Dr Gopa Raychaudhuri, "Facilitating Development of Gene Therapies for Rare Diseases," summarized all Gene Therapies approved by the US FDA. There were 19 approved gene therapies: 6 stem cell therapies, 6 T cell therapies, and 7 directly administered therapies.  

Gene therapy therapies are reviewed and approved by FDA Center for Biologicals Evaluation and Research (CBER), especially the Office of Therapeutic Products (OTP) - Approved Cellular and Gene Therapy Products are listed here. 

For each approved gene therapy, FDA publishes the product approval and review information on their website by year. The clinical evidence of effectiveness is provided to the public for transparency. For those 19 approved gene therapies, "Summary Basis for Regulatory Action" documents were reviewed and some basic information was summarized in the table below. 

Sponsor	Product & Indication	Study Design	Sample Size	FDA approval date/Brand Drug Name
Pfizer	Adeno-associated virus vector-based gene therapy.   Adults with moderate to severe hemophilia B.	Phase 1/2a Study C0371005 (Safety)  - open-label, single-dose, single-arm, multi-center.   Phase 3 Study C0371002 (Efficacy and Safety), open label, single-dose, multi-national study .   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/beqvez	15 subjects     45 subjects	April 2024 Beqvez
Orchard Therapeutics	Stem cell-based gene therapy.   Children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile, metachromatic leukodystrophy.	Data from an adequate and well-controlled investigation comprised of two single arm, single-center, open-label studies, a European Union Expanded Access Program (EAP), and one ongoing long-term follow-up study and a natural history study. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy	Study OTL-200-201222 (n=18) and Study 205756 (n=10)	March 2024 Lenmeldy
Vertex	Stem cell-based gene therapy-genome editing using CRISPR/Cas9 and SPY101. Patients aged 12 years and older with transfusion-dependent β-thalassemia (TDT).	Multinational, single-arm, open-label, phase 1/2/3 study. https://www.fda.gov/vaccines-blood-biologics/casgevy	52 dosed, 35 evaluable.	Jan 2024 Casgevy
Vertex	Stem cell-based gene therapy -genome editing using CRISPR/Cas9/SPY101 technology. Sickle cell disease in patients aged 12 years or older with recurrent vaso-occlusive crises.	Multinational, single-arm, phase 1/2/3 study.     https://www.fda.gov/vaccines-blood-biologics/casgevy	44 treated, 31 evaluable.	Dec 2023 Casgevy
Bluebird Bio	LVV gene therapy. Sickle cell disease in patients aged12 years or older with a history of vaso-occlusive events.	Study Hgb 206, an ongoing Phase 1/2, open label, multicenter. https://www.fda.gov/vaccines-blood-biologics/lyfgenia	Safety: 54 subjects.   Efficacy: 32 subjects.	Dec 2023 Lyfgenia
BioMarin	Adeno-associated virus vector-based gene therapy.   Adults with severe hemophilia A.	Open-label, single-dose, single-arm, multinational phase 3 study.   https://www.fda.gov/vaccines-blood-biologics/roctavian	112 subjects dosed and constituted the rollover population evaluated.	June 2023 Roctavian
Sarepta	Adeno-associated virus vector-based gene therapy. Ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.	Open-label study 101. Randomized, double-blind, placebo-controlled study 102. Open label study 103.  https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/elevidys	Safety: 85 subjects. 73 subjects received intended dose and 12 received lower doses.	June 2023 Elevidys
Krystal Biotech	Vector-based gene therapy.   Wounds in patients 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.	First-in-human, single-center, open-label, randomized, intra-subject, placebo (vehicle) controlled phase 1/2 study (KB103-001). Multicenter, intra-subject randomized, placebo-controlled, double-blind open-label phase 3 study (B-VEC-03). https://www.fda.gov/vaccines-blood-biologics/vyjuvek	9 subjects.           Safety: 31 subjects.	May 2023 Vyjuvek
Ferring Pharmaceuticals A/S	Vector-based gene therapy. Adult patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.	Single-arm trial study (CS-003).   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/adstiladrin	107 subjects enrolled. 98 subjects evaluable. Efficacy: 55 subjects.	Dec 2022 Adstiladrin
CSL Behring	Adeno-associated virus vector-based gene therapy.   Adults with Hemophilia B (congenital Factor IX deficiency).	Open-label, single-dose, single-arm, multi-center phase 2b study. Open-label, single-dose, multi-center, multinational phase 3 study. https://www.fda.gov/vaccines-blood-biologics/vaccines/hemgenix	3 subjects.     54 subjects.	Nov 2022 Hemgenix
Bluebird bio	Stem cell-based gene therapy. Slowing the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy.	Open-label, multicenter, single-arm phase 2/3 study. Open-label, multicenter, single-arm phase 3 study.   https://www.fda.gov/vaccines-blood-biologics/skysona	Safety: 67 subjects. Efficacy: 61 subjects.	Sept 2022 Skysona
Bluebird Bio	LVV Gene Therapy Beta-thalassemia. B cell maturation antigen-directed genetically modified. Adult and pediatric patients with ß-thalassemia who require regular red blood cell (RBC) transfusions.	Two open-label, multicenter, single-arm phase 3 studies. https://www.fda.gov/vaccines-blood-biologics/zynteglo	18 in HGB-212 study and 23 in HGB 207 study.	Aug 2022 Zynteglo
Janssen Biotech	Autologous T cell immunotherapy. Adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy.	Single-arm, phase 1b-2 multicenter study.   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/carvykti	Efficacy: 97 subjects.	Feb 2022 Carvykti
Celgene Corporation	B cell maturation antigen-directed genetically modified autologous T cell immunotherapy. Adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody	Single-arm, multicenter phase 2 study.   https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel	Safety: 127 subjects. Efficacy: 100 subjects.	March 2021 Abecma
Juno Therapeutics	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.	Single-arm, multicenter phase 1 study.   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel	Safety: 268 subjects. Efficacy: 256 subjects.	Feb 2021 Breyanzi
Kite Pharma	CD19-directed genetically modified autologous T cell Immunotherapy.   Adult patients with relapsed or refractory Mantle Cell Lymphoma.	Single-arm, multicenter, phase 2 study.   https://public4.pagefreezer.com/browse/FDA/27-12-2021T03:59/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel	68 subjects treated. Efficacy: 60 subjects.	July 2020 Tecartus
AveXis	Adeno-associated virus vector-based gene therapy.  Pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 gene.	Open-label, single-arm, ascending-dose, phase 1 study. Open-label, single-arm, phase 3 study. https://public4.pagefreezer.com/browse/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/zolgensma	15  subjects.     44 subjects.	May 2019 Zolgensma
Spark Therapeutics	Adeno-associated virus serotype 2 vector gene therapy.  Confirmed biallelic RPE65 mutation-associated retinal dystrophy.	Open-label, dose-escalation, phase 1 study. Open-label, randomized, controlled, cross-over, phase 3 study. https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna	12 subjects.   29 subjects.	Dec 2017 Luxturna
Kite Pharma	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy	Single-arm, open-label, multicenter phase 1/2 study.   https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel	Safety: 108 subjects. Efficacy: 101 subjects.	Oct 2017 Yescarta
Novartis Pharmaceuticals	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with relapsed or refractory follicular lymphoma after two or more lines of therapy.	Multicenter, open-label, single-arm, trial.   https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel	63 subjects.	Aug 2017 Kymriah

The clinical evidence for the effectiveness of gene therapies often comes from multi-center, open-label, single-arm studies with relatively small sample sizes, as shown in the table above. In some cases, phases of clinical development are combined.

FDA Office of Scientific Investigations (OSI) Requests for Bioresearch Monitoring (BIMO) Data for NDA/BLA Submission

FDA has a Bioresearch Monitoring (BIMO) program and the BIMO program is managed by the Office of Scientific Investigations (OSI). 

BIMO program is a comprehensive, FDA-wide program of on-site inspections and data audits, designed to monitor all aspects of the conduct and reporting of FDA-regulated research. 

Objectives of the BIMO program includes: 

• Protect the rights, safety, and welfare of human research subjects
• Verify the accuracy, reliability, and integrity of clinical and non-clinical trial data submitted to FDA
• Assess compliance with FDA's regulations governing the conduct of clinical and non-clinical trials, including regulations for informed consent and ethical review

BIMO program has become a cornerstone of the FDA preapproval process for new medicines, medical devices, food and color additives, veterinary products and, tobacco products introduced to the U.S. consumer.

The BIMO program also takes part in pharmacovigilance activities for postmarketing drug products. These activities serve to detect, understand, and prevent drug-related problems.

The BIMO program is managed and executed differently at different review centers (namely CDER and CBER). CBER's BIMO program was described in a FDA presentation by Dr Triet Tran "The Center for Biological Evaluation and Research (CBER) Bioresearch Monitoring (BIMO) Program". CDER's BIMO program was described in a Youtube video by Dr Kelly Nolen "Center for Drug Evaluation and Research (CDER) Bioresearch Monitoring (BIMO) Program - A General Overview".

For NDA or BLA submissions to CDER, sponsors are often asked to provide site-specific information to support the FDA’s Bioresearch Monitoring (BIMO) program and aid in selecting sites for inspection. The FDA typically includes standard language about this (see below) in their communications, such as in letters to the sponsor or the minutes of pre-NDA or pre-BLA meetings.

OFFICE OF SCIENTIFIC INVESTIGATIONS (OSI) REQUESTS

The Office of Scientific Investigations (OSI) requests that the items described in the draft guidance for industry, Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions, and the associated conformance guide, Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications, be provided to facilitate development of clinical investigator and sponsor/monitor/CRO inspection assignments, and the background packages that are sent with those assignments to the FDA ORA
investigators who conduct those inspections. This information is requested for all major trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials). Please note that if the requested items are provided elsewhere in submission in the format described, the Applicant can describe location or provide a link to the requested information.

Please refer to the draft guidance for industry Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications.

Sponsor's statistical programming group will need to prepare the BIMO related data sets and data listings - all by sites. 

• A data set containing general study related information and comprehensive clinical investigator information
• Subject level data listing by site
• Site level dataset

Details about BIMO datasets and data listings can be found in the FDA CDER guidance titled Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications (see the table of contents below). It’s important to note that this guidance applies only to CDER and not to other FDA review divisions like CBER. Since the BIMO technical conformance guide is regularly updated, the statistical programming team must ensure they are following the most current version when preparing the BIMO package for NDA or BLA submissions.

There has been extensive discussion about using SAS programming to generate the BIMO package, including the creation of BIMO datasets and data listings:

• BIMO Package: Challenges and Perspectives While Keeping Up with the Upgrades in the BIMO Technical Conformance Guide and the BDRG Guidelines 
• BIMO SAS® Macros and Programming Tools 
• Development of standard BIMO process to create clinsite dataset 
• Preparing a Successful BIMO Data Package 
• Bioresearch Monitoring (BIMO) Data Reviewer’s Guide 

Crossover design in confirmatory therapeutic trials

This week, FDA approved a new drug called Aqneursa (levacetylleucine) for the treatment of neurological symptoms associated with Niemann-Pick disease type C (NPC) - a rare disease - in adults and pediatric patients. FDA approval was based on the confirmatory phase 3 study using a crossover design. "The safety and efficacy of Aqneursa for the treatment of NPC were evaluated in a randomized, double-blind, placebo-controlled, two-period, 24-week crossover study. The duration was 12 weeks for each treatment period. The study enrolled 60 patients." The study design was discussed in the paper by Fields et al "N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study" and the crossover study design was depicted as below. Patients were assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 (levacetylleucine) followed by placebo or placebo followed by IB1001 (levacetylleucine). Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia

The advantages of the crossover design includes:

• It allows a within-patient comparison between treatments. Each patient serves as his/her own control
• Treatment contrasts estimated as a within subject effect
• Fewer subjects (smaller sample size) required for the study

The disadvantages of the crossover design includes: 

• Carryover effect of previous treatment to the next treatment
• Time dependent changes
• Increased time length of the trial
• Drop out issue, too many visits
• May require complicated statistical modeling - for example, mixed model to analyze the data

The crossover design is very common and almost the default design for bioequivalence studies. As stated in FDA's guidance for industry "Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA", crossover design was recommended in most of situations. 

"For most dosage forms that release a drug intended to be systemically available, FDA recommends that applicants perform a two-period, two-sequence, two-treatment, single-dose,crossover study using either healthy subjects or other populations, as appropriate. In this design, each subject should receive each treatment (the test and the reference product) in a random order. 

A replicate crossover study design (either partial or fully replicate) is appropriate for drugs  whether the reference product is a highly variable drug or not. A replicate design can have the advantage of using fewer subjects compared to a non-replicate design, although each subject in a replicate design study would receive more treatments."

However, crossover designs are seldom employed in confirmatory therapeutic clinical trials, which typically use clinical endpoints rather than pharmacokinetic ones. The most common design for these trials is the traditional randomized controlled trial (RCT) with parallel groups, where patients are randomly assigned to either an experimental treatment group or a placebo.

In some special situations such as the rare disease drug development, the crossover design may be employed in the phase 3 confirmatory clinical trials. Here are some examples: 

• Samsung Bioepis Co. "A Study to Compare SB12 (Proposed Eculizumab Biosimilar) to Soliris in Subjects With Paroxysmal Nocturnal Haemoglobinuria" - the product" - FDA approved the product based on this study with crossover design
• KalVista Pharmaceuticals "A Phase III, Crossover Trial Evaluating the Efficacy and Safety of KVD900 for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE)" - NDA based on this study is under FDA's review
• GSK "Cross-Over Study in Subjects With COPD, Evaluating Lung Function Response After Treatment With Once Daily Umeclidinium 62.5mcg, Vilanterol 25mcg, and Umeclidinium/​Vilanterol 62.5/​25mcg"
• Wiley et al (2016) "A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema"
• Bethoux et al (2024) "A randomized, double-blind, placebo-controlled trial to evaluate the effect of nabiximols oromucosal spray on clinical measures of spasticity in patients with multiple sclerosis"  
• Watz et al (2016) Effects of indacaterol/glycopyrronium (QVA149) on lung hyperinflation and physical activity in patients with moderate to severe COPD: a randomised, placebo-controlled, crossover study (The MOVE Study)
• Zhang et al (2022) Design and analysis of crossover trials for investigating high-risk medical devices: A review

ICH E9 "STATISTICAL PRINCIPLES FOR CLINICAL TRIALS" have a section discussing crossover design:

FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications" also discussed the advantages and disadvantages of the crossover design:

In confirmatory therapeutic trials using a crossover design, an additional concern is the potential for unblinding. As the same patient receives both the experimental drug and the placebo, the patient might be able to identify or guesstimate the treatment group they are assigned to based on slight differences in taste, smell, or side effects.

The Role of Radiolabeling in Clinical Studies: Exploring Lung Deposition and Mass Balance Studies

Radiolabeling is an advanced and valuable technique in clinical research that enables scientists to trace the journey of drugs through the human body. By attaching a radioactive isotope to a drug molecule (usually a small molecule), researchers can track its absorption, distribution, metabolism, and excretion (ADME). This technique provides precise, real-time data and is especially useful for two types of clinical studies: lung deposition studies and mass balance studies.

What Are Lung Deposition Studies?

Inhaled medications are commonly used to treat respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, and cystic fibrosis. However, the efficacy of these treatments largely depends on how much of the drug reaches the target area in the lungs.

Lung deposition studies assess the distribution of inhaled drugs within the lungs. The primary goal of these studies is to ensure that the drug particles deposit in the right lung regions for optimal therapeutic effect. Radiolabeling plays a crucial role in these studies by enabling researchers to visualize and quantify how inhaled drugs spread through the respiratory system.

Radiolabeling in Lung Deposition Studies

Radiolabeling in lung deposition studies involves attaching a radioactive isotope, such as technetium-99m (99mTc), to the drug formulation. After inhalation, the radioactive emissions from the drug particles are detected using imaging techniques like gamma scintigraphy or positron emission tomography (PET). These images provide a detailed map of drug distribution within the lungs.

Key advantages of using radiolabels for lung deposition studies include:

• Accurate Measurement: Researchers can measure how much of the drug reaches the lungs and where exactly in the lungs it settles (central airways, peripheral airways, alveoli, etc.).
• Device Optimization: By studying how well different inhaler devices (e.g., dry powder inhalers, metered-dose inhalers, nebulizers) deliver the drug, researchers can refine device designs to improve drug delivery to the lungs.
• Personalized Treatment: Lung deposition patterns vary across individuals due to differences in lung anatomy, disease severity, and inhaler technique. Radiolabeling helps researchers tailor treatments to individual needs.

Imaging Techniques in Lung Deposition Studies

1. Gamma Scintigraphy: This is the most commonly used imaging method in lung deposition studies. It detects gamma radiation emitted from radiolabeled drug particles and generates detailed images showing how much of the drug is deposited in different parts of the lungs.

2. Positron Emission Tomography (PET): PET is a more advanced imaging technique that uses isotopes like carbon-11 to provide high-resolution, three-dimensional images of drug distribution in the lungs. While more expensive and complex than gamma scintigraphy, PET can offer more precise data on drug uptake and metabolism in the lungs.

Why Lung Deposition Studies Matter

• Efficacy: Lung deposition studies help determine if a drug reaches the specific areas of the lungs (for example, the peripheral part of the lung versus central part of the lung) where it's needed most. For example, drugs intended for deep lung penetration must reach the alveoli to be effective.
• Safety: By ensuring that a drug is delivered directly to the lungs and not to other parts of the body, these studies minimize systemic side effects.
• Regulatory Compliance: Regulatory agencies like the FDA and EMA often require data on drug deposition patterns to ensure safety and efficacy, especially for inhaled drugs.

Some Examples of the Lung Deposition Studies: 

• Brand et al (2009) Lung deposition of inhaled α1-proteinase inhibitor in cystic fibrosis and α1-antitrypsin deficiency ERJ
• Brank et al (2007) Lung Deposition of Radiolabeled Tiotropium in Healthy Subjects and Patients With Chronic Obstructive Pulmonary Disease  Journal of Clinical Pharmacology
• Van Holsbeke et al (2018) Use of functional respiratory imaging to characterize the effect of inhalation profile and particle size on lung deposition of inhaled corticosteroid/longacting beta2-agonists delivered via a pressurized metered-dose inhaler. Ther Adv Respir Dis 

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What Are Mass Balance Studies?

Mass balance studies, also known as absorption, distribution, metabolism, and excretion (ADME) studies, track the fate of a drug from administration to elimination. These studies are essential for understanding how much of the drug is absorbed into the bloodstream, how it is metabolized, and how it is excreted from the body.

Radiolabeling is critical in mass balance studies as it enables precise quantification of the drug and its metabolites in different biological samples, including blood, urine, feces, and sometimes breath.

Radiolabeling in Mass Balance Studies

In mass balance studies, radiolabeling involves attaching a radioisotope (such as carbon-14 or tritium) to the drug molecule. Once the drug is administered, researchers can track its movement through the body by measuring radioactive emissions in collected biological samples. The use of radiolabels allows for accurate and complete recovery of the drug and its metabolites, making it easier to determine:

• Total absorption: How much of the drug is absorbed into systemic circulation.
• Metabolic pathways: How the drug is broken down in the body and the metabolic products formed.
• Elimination: The routes through which the drug is excreted (e.g., urine, feces) and how much is removed from the body over time.

According to FDA guidance for industry (2024) "Clinical Pharmacology   Considerations for  Human Radiolabeled Mass Balance Studies", the following were stated:

A human radiolabeled (most commonly 14C or 3H) mass balance study is the single most direct method to obtain quantitative and comprehensive information on the absorption, distribution, metabolism, and excretion (ADME) of the drug in the human body.  

The mass balance study can provide information to: 

• Determine the overall pathways of metabolism and excretion of an investigational drug 
• Identify circulating metabolites 
• Determine the abundance of metabolites relative to the parent drug or total drug-related exposure 

The results from mass balance studies help to: 

• Provide information on which metabolites should be structurally characterized and which metabolites should undergo nonclinical safety assessment or drug-drug interaction (DDI) evaluation 
• Assess whether renal or hepatic impairment studies or certain DDI studies are recommended for the investigational drug 
• Assess the extent of absorption of the investigational drug 

Importance of Mass Balance Studies

1. Drug Safety: Mass balance studies help identify any potentially harmful metabolites that could lead to side effects. By understanding how a drug is metabolized, researchers can predict interactions with other medications.

2. Dose Optimization: These studies provide critical information for determining appropriate dosage levels by understanding how much of the drug remains in the system over time.

3. Regulatory Approval: Mass balance data is essential for regulatory submissions, providing authorities with a full picture of the drug’s pharmacokinetics and safety profile.

Challenges in Radiolabeled Mass Balance Studies

Although radiolabeling offers precise tracking of drugs, mass balance studies present a few challenges:

• Complexity: Preparing radiolabeled drugs requires specialized equipment and expertise, which can increase the cost and time required for studies.
• Radiation Safety: Even though radiolabels use minimal radiation doses, strict safety protocols must be followed to minimize exposure risks for study participants and researchers.
• Variability: Individual differences in metabolism can lead to variability in study results, requiring large sample sizes for accurate interpretation.

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Combining Lung Deposition and Mass Balance Studies

Radiolabeling enables researchers to link data from both lung deposition and mass balance studies. For inhaled drugs, this combined approach provides a complete picture of how the drug behaves after delivery: from deposition in the lungs to its absorption into the bloodstream and eventual elimination.

Conclusion

Radiolabeling plays a pivotal role in both lung deposition and mass balance studies, providing detailed, real-time insights into the distribution and metabolism of drugs within the body. These studies are indispensable for the development of safe and effective therapies, particularly for inhaled medications and other drugs that require precise delivery to target tissues.

By combining data from lung deposition studies with mass balance studies, researchers can optimize drug formulations, refine delivery devices, and ensure that new drugs meet regulatory requirements, all while enhancing patient outcomes.

Patents vs. Trade Secrets: Understanding the Best Approach for Your Innovation and Invention

In today’s competitive business landscape, protecting intellectual property (IP) is critical. Whether you’re an inventor developing a groundbreaking drug product or a company refining proprietary processes, understanding how to safeguard your creations is essential. Two key ways to protect intellectual property are patents and trade secrets. While both offer avenues to safeguard your innovations, they differ significantly in scope, cost, and long-term strategy. Here are the differences between patents and trade secrets.

What is a Patent?

A patent is a government-issued right that grants an inventor exclusive control over their invention for a limited time. It essentially provides a legal monopoly, preventing others from making, using, or selling the patented invention without permission.

Patents typically last 20 years (for utility patents) from the date of filing. During this time, the inventor has the right to license the invention, sell the patent rights, or enforce their exclusive ownership through legal channels. If clinical development takes a very long time, the remaining patent protection may be limited by the time the product is approved. After patents expire, the generic drugs may be brought to the market.

Key Features of Patents:

• Full Disclosure: When you file for a patent, you must disclose every detail about your invention to the public. This ensures that once the patent expires, others can build upon or use the invention.
• Protection Scope: Patents cover new and useful inventions, processes, or designs. Examples include novel machinery, medical devices, or software algorithms.
• Legal Enforceability: Patents can be enforced through lawsuits against infringers. If someone tries to use your invention without permission, you can seek legal redress.
• Costs: The costs associated with obtaining and maintaining a patent can be substantial, including filing fees, legal fees, and periodic maintenance fees over the life of the patent.

Example of a Patent: The iPhone, for example, is covered by thousands of patents, including both the hardware and software innovations.

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What is a Trade Secret?

A trade secret, on the other hand, is information that companies keep confidential to maintain a competitive advantage. Unlike patents, which require public disclosure, trade secrets thrive on secrecy. As long as the information remains secret and is valuable to the business, the protection can last indefinitely.

Unlike patents, trade secrets are not registered with any governmental agency. Instead, businesses take steps to keep the information secure—through non-disclosure agreements (NDAs), security protocols, and restricting access to the secret.

Key Features of Trade Secrets:

• Confidentiality: The defining characteristic of a trade secret is its secrecy. If the secret becomes public, the protection is lost.
• Indefinite Duration: As long as the secret is kept confidential, protection can last indefinitely. For example, the Coca-Cola formula has been protected for over a century.
• Lower Costs: Trade secrets don’t require the extensive costs associated with patents, though companies need to invest in maintaining secrecy, such as through legal contracts and security measures.
• Risk of Exposure: Trade secrets are vulnerable to accidental disclosure, reverse engineering, or independent discovery. If a competitor uncovers your secret by lawful means, you lose your exclusive advantage.

Example of a Trade Secret: The Coca-Cola formula is one of the most famous trade secrets, kept under tight security since the late 1800s. Also see Famous Trade Secrets in Business History and 5 Famous Trade Secrets People Use Everyday.

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Comparing Patents and Trade Secrets

	Patent	Trade Secret
Issued by	The United States Patent and Trademark Office (USPTO) – a government agency in the U.S. Department of Commerce Other corresponding agencies in other countries	None
Disclosure	Full public disclosure is required.	No disclosure; must remain confidential.
Duration	Limited to 20 years from the date of filing for utility patents.	Indefinite, as long as secrecy is maintained.
Cost	High, including filing and legal fees.	Low, mainly for maintaining security and contracts.
Protection Scope	Protects inventions, processes, or designs.	Protects confidential business information.
Enforcement	Legal enforcement through patent infringement lawsuits.	Legal action against theft or breach of contract.
Risk	After expiration, the invention enters public domain.	Vulnerable to exposure through reverse engineering or independent discovery.

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Choosing Between a Patent and a Trade Secret

When deciding between a patent and a trade secret, the nature of your invention, business strategy, and budget should guide your decision. Here are some questions to help you decide:

1. Do you want long-term protection?
• If your invention can be kept secret indefinitely and the risk of reverse engineering is low, a trade secret might be ideal. However, if public disclosure doesn’t harm your competitive advantage and your innovation is at risk of duplication, a patent offers legal protection for 20 years.
2. How costly is it to protect your innovation?
• Patents come with significant costs—filing fees, legal representation, and maintenance fees. For small businesses or startups, these costs can be prohibitive. In contrast, trade secrets require less upfront investment but need ongoing vigilance in maintaining confidentiality.
3. Will your innovation be reverse-engineered?
• If your innovation can easily be reverse-engineered or independently discovered (like a consumer product), a patent provides stronger protection. On the other hand, if your business relies on internal processes or formulas that competitors would struggle to uncover, a trade secret might be sufficient.
4. How much risk can you tolerate?
• Patents offer more certainty in protection, but once the patent expires, anyone can use the invention. Trade secrets are riskier, as they rely on maintaining secrecy, but they can offer indefinite protection as long as no one else uncovers the secret.

In the pharmaceutical and biotechnology industries, patents are the primary tool for safeguarding intellectual property. Trade secrets, on the other hand, can be challenging to maintain, especially with the frequent movement of scientists between companies.

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Conclusion

Both patents and trade secrets offer powerful tools for protecting your intellectual property, but each has its strengths and weaknesses. A patent is ideal when you want strong, enforceable protection and are willing to disclose your invention in exchange for a limited monopoly. Trade secrets, on the other hand, work best when you can keep an innovation confidential and want to avoid the high costs of patenting.

Ultimately, the choice between patents and trade secrets comes down to your specific needs, the nature of your innovation, and how you plan to leverage your competitive advantage in the marketplace. In many cases, businesses use both strategies (plus also the FDA exclusivity) to protect different aspects of their intellectual property, ensuring they maximize protection while minimizing risk.

Good Reading: 

• Nealey, Daignault, and Cai (2015) Trade Secrets in Life Science and Pharmaceutical Companies
• Trade secrets: a strategic element in the life sciences and biotechnology industries

Understanding Patent and FDA Exclusivity: Protecting Innovation and Encouraging Drug Development

In the world of pharmaceuticals, innovation is the lifeblood of progress. Developing a new drug is an incredibly complex and expensive process, often taking over a decade and costing billions of dollars. To encourage this kind of investment, the U.S. legal and regulatory system provides mechanisms to protect and reward the creators of new drugs. Two of the most critical tools in this arsenal are patent protection and FDA exclusivity. While they serve different purposes and are governed by different bodies, together they create a robust framework that supports pharmaceutical innovation.

What is a Patent?

A patent is a form of intellectual property protection granted by the U.S. Patent and Trademark Office (USPTO). It gives the patent holder the exclusive right to make, use, sell, or distribute an invention for a set period, typically 20 years from the date of filing. The purpose of a patent is to incentivize innovation by giving inventors a temporary monopoly, allowing them to recoup their investment and profit from their ingenuity.

In the pharmaceutical industry, patents can cover various aspects of a drug, including the active chemical compound, the formulation, the method of manufacturing, and even the method of use. For example, a company might patent a novel drug molecule, but they could also seek patents for a specific drug delivery system or a new therapeutic use for an existing drug.

However, it’s important to note that a patent alone does not give a company the right to market a drug. The drug must still undergo the rigorous approval process overseen by the U.S. Food and Drug Administration (FDA). This is where FDA exclusivity comes into play.

What is FDA Exclusivity?

FDA exclusivity refers to the period during which the FDA grants a drug manufacturer the sole right to market a drug. This exclusivity is separate from and independent of any patent protection. The FDA awards exclusivity to incentivize drug development, especially in areas where there is a significant unmet medical need.

The length and type of exclusivity vary depending on the nature of the drug and its approval pathway:

• New Chemical Entity (NCE) Exclusivity: Granted to drugs containing an active moiety that has never been approved by the FDA. This provides 5 years of exclusivity.
• Orphan Drug Exclusivity: Awarded to drugs that treat rare diseases affecting fewer than 200,000 people in the U.S. This offers 7 years of exclusivity.
• Pediatric Exclusivity: Provides an additional 6 months of exclusivity if the manufacturer conducts FDA-requested pediatric studies.
• Biologics Exclusivity: Under the Biologics Price Competition and Innovation Act (BPCIA), biologics are granted 12 years of exclusivity.

During the exclusivity period, the FDA cannot approve any generic versions of the drug, even if the original drug’s patents have expired. This creates a significant commercial advantage for the innovator, allowing them to maximize their return on investment.

Here are some useful links discussing the patent and FDA exclusivity:

• Frequently Asked Questions on Patents and Exclusivity
• FDA presentation: Exclusivity–Which one is for me?
• FDA/CDER SBIA Chronicle: Patents and exclusivity
• The FDA Law Blog Articles related to Patents and exclusivity

The Interplay Between Patents and FDA Exclusivity

While patents and FDA exclusivity both serve to protect new drugs, they do so in different ways and often overlap. A new drug may have several patents associated with it, protecting various aspects of the invention. However, these patents may expire before the FDA exclusivity does, or vice versa.

For instance, a drug might be protected by a patent on its active ingredient, which expires 15 years after the drug is approved. However, if the drug is also granted FDA exclusivity, the manufacturer might enjoy additional years without competition, even after the patent expires.

This interplay becomes particularly significant when considering the entry of generic drugs into the market. Generic manufacturers often challenge the validity of patents or wait for them to expire before seeking FDA approval. However, they must also wait for any FDA exclusivity periods to lapse before they can launch their generic versions, which can significantly delay their market entry.

The Impact on Innovation and Access

The combination of patents and FDA exclusivity creates a delicate balance between encouraging innovation and ensuring that patients have access to affordable medications. On one hand, these protections are essential for incentivizing pharmaceutical companies to invest in research and development. Without the prospect of a temporary monopoly, the financial risk associated with drug development might outweigh the potential rewards, leading to fewer new drugs entering the market.

On the other hand, extended periods of market exclusivity can delay the availability of lower-cost generic drugs, impacting patients’ access to affordable treatments. This tension is at the heart of ongoing debates about drug pricing and healthcare policy.

Patent vs. FDA Exclusivity – a Comparison

Aspect	Patent	FDA Exclusivity
Definition	Legal protection granted for an invention, giving the holder the right to exclude others from making, using, or selling the invention for a certain period.	Market exclusivity granted by the FDA to a drug manufacturer, preventing competitors from entering the market with similar products.
Governing Body	U.S. Patent and Trademark Office (USPTO)	U.S. Food and Drug Administration (FDA)
Issuing & Granting	Patents can be issued or expire at any time regardless of the drug's approval status	Exclusivity can be granted upon approval of a drug product if the statutory requirements are met.
Enforceable	a patent in the United States is only enforceable in the United States. To enforce a patent in other countries, you have to obtain a patent in those foreign countries	FDA exclusivity is only applicable in the United States. Other countries may have their own exclusivities. For example, The European Medicines Agency (EMA) has two types of exclusivity for medicines: data exclusivity and market exclusivity
Purpose	To incentivize innovation by protecting intellectual property.	To encourage the development of new drugs and to reward clinical research, especially for rare diseases or conditions.
Duration	20 years from the filing date of the patent application (can vary slightly depending on the type of patent).	Varies by type: 6-month for six-month "pediatric exclusivity." 5 years for new chemical entities, 7 years for orphan drugs, 3 years for changes in previously approved drugs, and up to 12 years for biologics.
Cost for maintenance	In order to maintain the enforceability of the utility Patent,  maintenance fees must be paid at regular intervals throughout the 20-year term of the Patent.	No fees for receiving the exclusivity. Fees (PDUFA Fees) may be paid for NDA/BLA submission
Scope	Protects the invention itself, which could be a drug, a process, a device, or a formulation.	Provides exclusive marketing rights in the U.S., blocking generic competition regardless of patent status.
When It Starts	From the date the patent is filed (though it becomes enforceable upon approval). If the drug development takes a long time, the patent protection period will be significantly shortened by the time of the drug approval	Starts when the FDA approves the drug for marketing.
Eligibility	Must meet patentability criteria: novelty, non-obviousness, and usefulness.	Dependent on FDA approval for new drugs, orphan drugs, biologics, or significant changes to existing drugs.
Extension Possibility	Possible through mechanisms like patent term extension (PTE) under the Hatch-Waxman Act, typically for up to 5 years.	Exclusivity periods are generally fixed but can be extended under certain conditions, like pediatric exclusivity (additional 6 months).
Effect on Market	Prevents others from making or selling the patented product or process, potentially creating a monopoly.	Prevents the FDA from approving generic versions or biosimilars, maintaining market exclusivity for the brand-name drug.
Impact of Expiry	After expiry, competitors can produce and market the product, assuming no other patents or exclusivities apply.	After expiry, generic or biosimilar competitors can be approved and enter the market.

Conclusion

In summary, patent protection and FDA exclusivity are two critical tools that work together to support pharmaceutical innovation. While patents protect the intellectual property of drug inventions, FDA exclusivity ensures that innovators have a period of time to market their drugs without competition. Understanding the nuances of these mechanisms is essential for anyone involved in the pharmaceutical industry, from researchers and developers to policymakers and healthcare providers.

By carefully navigating the landscape of patents and FDA exclusivity, pharmaceutical and biotechnology companies can maximize the value of their innovations while contributing to the advancement of medical science and the improvement of public health.

Estimand Framework - discussions at JSM 2024

In the Joint Statistical Meetings 2024, there was a session "Global Impact of the ICH E9(R1) Addendum - 5-Year Anniversary for the Trial Estimand Framework". In this session, panel members discussed the global impact of this guidance at its 5-year anniversary. Members from different regulatory agencies and the pharmaceutical industry, including members from the ICH E9(R1) Expert Working Group, reflected on multiple aspects of the impact of the estimand framework and the current stage of its broad implementation across clinical trials, including:

• impact of the estimand framework to regulatory interactions, trial planning, drug approval process and labeling
• examples of estimand framework implementation
• disease-specific regulatory guidance documents using the estimand framework, including future plans
• implementation of the ICH E9(R1) Addendum in clinical trial practice, from start (planning a trial, protocol development) to finish (reporting, communication and dissemination of results) and any remaining challenges
• estimand thinking process and multi-disciplinary collaborations
• estimand-related initiatives and their global impact
• development of statistical methodologies (e.g. missing data and causal inference methods) triggered by the ICH E9(R1) Addendum;
• standardizations efforts that facilitate the implementation of this framework; opportunities for the future.

The ICH E9(R1) guideline has been formally endorsed by major regulatory agencies such as the EMA, FDA, HC, and PMDA. The concepts of estimands and intercurrent events are frequently addressed in regulatory feedback on study protocols and statistical analysis plans. However, these topics have yet to gain traction in disease-specific scientific conferences. For instance, at several conferences and congresses focused on cardiovascular and pulmonary diseases, I observed a notable absence of presentations or abstracts discussing the estimand framework. Within the industry, estimands and intercurrent events are often seen as purely statistical concepts, primarily relevant to statisticians.

Estimand: A precise description of the treatment effect reflecting the clinical question posed by the trial objective. It summarises at a population-level what the outcomes would be in the same patients under different treatment conditions being compared. 

Estimator: A method of analysis to compute an estimate of the estimand using clinical trial data.

Estimate: A numerical value computed by an estimator. 

A question arose regarding the lack of an appropriate estimator for the corresponding estimand. Stephen Ruberg, from the audience, provided an insightful response by quoting John Tukey: 'An approximate answer to the right problem is worth a good deal more than an exact answer to an approximate problem. The greatest value of a picture is when it forces us to notice what we never expected to see. An approximate answer to the right question is worth far more than a precise answer to the wrong one.' In the context of the estimand framework, it is crucial to ask the right question and define the estimand accurately. While an exact estimator for the proposed estimand may not exist, it can often be reasonably approximated.

The estimand framework has been built into some disease-specific regulatory guidance documents. For example, in FDA's guidance for industry "Graft-versus-Host Diseases: Developing Drugs, Biological Products, and Certain Devices for Prevention or Treatment", the estimand and intercurrent events are extensively discussed and example estimands are provided.