Ocugen’s expanded access program (EAP) is an open-label (information is not withheld from participants; in particular, both the researchers and participants know which treatment is being administered), singlearm, multicenter program providing COVAXIN™, an investigational drug product developed in India to combat serious illness, hospitalization, or death as a result of SARS-CoV-2 infection (aka COVID-19), which has led to a global pandemic. A Phase 3 randomized, double-blind study evaluating lot-to-lot immunogenicity in adults (age ≥18 years) who were healthy or had stable chronic medical conditions showed COVAXIN™ to be an effective vaccine countering the effects of SARS-CoV-2 infection. Overall vaccine efficacy of 77.8% (95% CI: 65.2–86.4), efficacy against severe disease and hospitalization of 93.4% (95% CI: 57.1–99.8); efficacy against symptomatic disease of 63.6% (95% CI: 29.0 – 82.4) was demonstrated. The vaccine was well tolerated in this study with a statistically significant safety outcome of 12.4% reported adverse events (AEs) in both the vaccine and placebo arms (p<0.05)1 Additionally, AEs following immunization (AEFI) collected in India after the administration of 59.9 million doses just over six months (16January-2021 to 6-August-2021) found only 1 serious adverse event (SAE) potentially associated with infection and has confirmed the safety findings from COVAXIN™ Phase 1-3 studies.2
Since the start of the pandemic, several prominent variants have been identified including Alpha (B.1.1.7) (United Kingdom [UK]); Beta (B.1.351) (South Africa); Gamma (P.1) (Japan/Brazil); and Delta (B.1.617.2) (India). COVAXIN™ demonstrated 65.2% efficacy against Delta (95% CI: 33.1-83.0) from the Phase 3 study. This was the first Phase 3 clinical trial to include Delta variant data. As of January 2022, approximately 99% of the dominant variant, Omicron (B.1.1.529 and BA lineages) is noted as being the most contagious SARSCoV-2 strain yet. Individuals infected with Omicron can spread the virus before symptoms appear, even if they are vaccinated.3 First reported in November 2021, Omicron was designated as a variant of concern (VOC) shortly after its dramatic spread in South Africa. Compared to the Delta variant which has 9 mutations, the Omicron variant has up to 59 mutations throughout its genome.4 Thirty-six of these mutations occur within the spike protein, the primary mechanism to host cell entry, and the target of the currently approved vaccines in the US. Fifteen of these mutations occur within the Omicron receptor binding domain (RBD) and may interfere with antibody binding and neutralization.4 Additional reports suggest that 13 of Omicron’s mutations appear as 3 clusters on the spike protein, are considered extremely rare in coronaviruses, and represent a substantial viral evolution.3 In a Phase 3 randomized double-blind placebo-controlled study which evaluated the immunogenic potential of COVAXIN™, 79 variants (included Delta) were reported from 16,973 samples resulted in an overall vaccine efficacy of 70.8%. In this same study the SARS-CoV-2 binding antibody titers to the S1-protein, the RBD and N-protein were detected after 2 doses and when measured as neutralizing antibodies across 3 lots of BBV152, showed consistent inducement of humoral response. Additionally, when measured as enzyme-linked immunosorbent assay (ELISA) IgG responses against the 3 epitopes, antibody titers were similar across all lots.1
Another study conducted at Emory University used a live virus neutralization assay to evaluate the neutralizing activity against the Omicron variant of sera collected from adults who received a booster dose 6 months after a primary series of COVAXIN™. The assay showed neutralization activity against D614G (vaccine strain), Delta and Omicron variants. Activity against the Delta variant was 100% of boosted recipients with >90% neutralizing activity against Omicron. Geometric mean neutralization titers were reduced by 1.5-fold and 9.4-fold against the Delta and Omicron variants respectively compared to the vaccine strain. This data suggests that booster doses of COVAXIN™ may be an effective addition to the COVID-19 vaccine arsenal.5
To date over 350 million doses of COVAXIN™ have been administered. The vaccine is authorized for emergency use in twenty-five countries with pending authorizations in more than sixty countries. And as many as one-hundred-ten countries agree to mutual recognition of COVID-19 vaccination certificates with India which include COVAXIN™. Emergency Use Authorization (EUA) was granted to COVAXIN™ by the World Health Organization (WHO) on November 3, 2021, based on review of data quality, safety, and efficacy.6 Further, the Technical Advisory Group (TAG) convened by WHO determined that COVAXIN™ meets WHO standards for protection against COVID-19 and with benefits outweighing risks and that COVAXIN™ can be used globally (WHO). Despite the FDA rejecting EUA in children 2 to 18 years of age, a recent publication in The Lancet on the immunogenicity and reactogenicity in this age group interpreted data suggesting COVAXIN™ was well-tolerated and induced higher neutralizing antibody responses that those seen in adults from the previously aforementioned Phase 3 study. 1,7
COVAXIN™ is currently being evaluated in a US population in a randomized, observer-blind, placebo-controlled immuno-bridging, and broadening study to demonstrate the equivalence of the immune response between participants enrolled in Phase 3 efficacy trial in India and demographically diverse healthy adult participants in the US which matched in age and vaccine formulation setting to whom those efficacy results are extrapolated; and to assess the broadening of the COVAXIN™ in participants who previously received two shots of messenger ribonucleic acid (mRNA) COVID-19 vaccine at least 6 months earlier or one-shots of viral vector J&J/Janssen COVID-19 vaccine at least 2 months earlier. Safety and tolerability evaluation is a secondary endpoint.8
Despite overall vaccinations against COVID-19, as of 23-May-2022, the total number of COVID-19 cases and deaths reported in the US were 83,145,591 and 999,384 respectively. Unvaccinated individuals ≥12 years of age have 3.1 times the risk of testing positive for COVID-19 infection and 20 times the risk of dying from COVID-19 compared to fully vaccinated individuals. To date, ~ 221 million people (~ 67% of the population) in the US have been fully vaccinated.9
COVAXIN™ is highly purified and comprises an inactivated whole virus and as such, retains the full antigenic representation of the virus including the spike protein (S), nucleocapsid protein (N), membrane protein (M), envelope protein (E), and the receptor binding domain (RBD). The retention of the inactivated virus onto Algel-IMDG and delivery of this array of critical viral proteins elicits a broad range of immune responses to the virus, including the potential for eliciting antibody response to conformational epitopes and escape mutants inactivated product. COVAXIN™ is a translucent liquid free from particulate matter for intramuscular injection administered as a series of two doses (0.5 mL each) at 4 weeks apart. The drug product is filled into 5 mL glass multi-dose vials and sealed with rubber stoppers. COVAXIN™ multipledose vial should be stored in original cartoons to protect contents from light at 2-8°C and should not be frozen. After the first dose has been withdrawn from a multi-dose vial, the adulterated vial shall be held between 2-8°C. Once opened, multi-dose vials should be used as soon as possible and within 6 hours when stored at 2-8°C. To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, health professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.
EXPANDED ACCESS PROGRAM (EAP)
COVAXIN™ will be available to participants in the US who are otherwise deemed ineligible for participation in a COVAXIN™ clinical trial. Ocugen will consider making COVAXIN™ available through the EAP only after the COVAXIN™ clinical trial begins and only in response to a written request from a licensed treating physician or infectious disease expert. The decision to grant or deny a written request is at the sole discretion of Ocugen. Ocugen cannot guarantee approval of any written requests. If a written request is approved, to the extent allowed by applicable law, regulations and, patient informed consent, Ocugen mandates the requesting physician ensures Ocugen receives scientific and clinical data tied to the physician’s use of the IDP. The decision to approve or deny a written request may be modified or reversed at any time by Ocugen and is subject to Ocugen’s ongoing evaluation of safety and efficacy data obtained from use of the IDP on a case-by-case basis. This decision to modify or reverse a written request may also be contingent on other factors related to chemistry, manufacturing, and controls (CMC), inventory, and the COVAXIN™ clinical development program. Ocugen may revise or rescind its policy on the EAP at any time.
HOW TO APPLY FOR THE COVAXIN™ EAP10
Step 1: Treating physician/infectious disease expert registers a written request with Ocugen.
- To review eligibility information, please see below.
- If you determine you meet the criteria, email: email@example.com.
- Our company representative will send you an information form and confidentiality agreement within 2 business days. This paperwork needs to be completed by the treating physician/infectious disease expert.
- Once the information form is returned to Ocugen, Ocugen will provide a response to the treating physician/infectious disease expert with a decision within 5 business days.
- With approval to participate, Ocugen will provide:
- A Letter of Authorization (LOA) to reference the active Investigational New Drug Application for manufacturing and nonclinical and clinical information.
- The COVAXIN™ expanded access clinical protocol.
- Proceed to Step 2.
Step 2: Treating physician/infectious disease expert submits a non-emergency individual patient investigational new drug (IND) application to FDA.
- Complete FDA Form 3926 as described in the instructions.
- Submit LOA and FDA Form 3926 using the Expanded Access eRequest.
Step 3: Obtain Institutional Review Board (IRB) approval to proceed under EAP per 21 CFR Part 56.
- Prepare written informed consent form (ICF).
- Obtain informed consent from the patient or their legally authorized representative per 21 CFR Part 50 using the written ICF approved by IRB.
Step 3: Begin treatment 30 days after IND application is received by FDA (or earlier if notified by FDA).
Step 4: File follow up reports using FDA Form 3926 to update FDA on the patient’s progress.
OCUGEN DECISION CRITERIA ON COVAXIN™ EAP APPROVAL
In general, Ocugen considers whether…
- Children 2-18 years of age or adults ≥ 18 and ≤ 65 years old, is at high risk for serious illness, hospitalization, or death from infection with SARS-CoV-2 or any known variants
- The patient has had previously documented positive polymerase chain reaction (PCR, or RT-PCR) test within 6 months
- The patient is ineligible or otherwise unable to participate in any clinical study involving Ocugen’s COVAXIN™ development program for that patient’s risk for SARS-CoV-2 infection;
- Alternative vaccine options are available and have been used in a primary series;
- Clinical data are available to assess the potential benefits and risks in providing COVAXIN™;
- The potential benefits to the patient justify the potential risks of COVAXIN™, and the risks are not unreasonable in the context of other SARS-CoV-2 vaccines;
- It is reasonable and appropriate, from a clinical and scientific perspective, to administer COVAXIN™ to a particular patient;
- The use of COVAXIN™ will be monitored and controlled appropriately and adequately by a licensed treating physician/infectious disease expert;
- The licensed physician/infectious disease expert under whose control COVAXIN™ will be administered is sufficiently qualified in terms of experience and credentials, administer vaccines in a safe manner;
- The site at which COVAXIN™ will be administered has the capability, including adequate facilities, equipment, and personnel, to provide any care for the patient needed following administration of COVAXIN™ should hypersensitivity or anaphylaxis occur;
- With the possible approval of the written request for COVAXIN™, there would remain sufficient supply of investigational drug product for ongoing and planned clinical trials;
- The approval of the written request would affect or interfere with the initiation, conduct, or completion of clinical trials, or otherwise compromise the potential development and/or commercialization of the investigational drug product;
- COVAXIN™ is part of an active clinical development program at Ocugen;
- An adequate supply and distribution logistics process exists for the investigational drug product;
- Ocugen can reach agreement with the requesting physician and/or the applicable site regarding an appropriate expanded access agreement satisfactory to Ocugen; and
- The written Request, and Ocugen’s approval of the written request, would be compliant with applicable local, state/provincial, and federal/national laws and regulations, as well as industry standards.
NOTE: Ocugen may require up to 5 business days to acknowledge receipt of the written request and will provide a written response to all written requests in a timely manner. Certain factors may affect the length of the review period and may include but are not limited to obtaining permission from regulatory authorities, the need for additional information from the requestor, or other factors beyond Ocugen’s control. Ocugen recognizes that the decision to approve or deny a written request is complex and will assist where possible to make the process smooth and seamless. Ocugen commits to: (i) conduct a clinical review of all written requests by an appropriate medical officer, (ii) decide each written request in an equitable and fair manner, and (iii) use the available scientific and clinical evidence in making each decision.
1Ella, R., Reddy, S., Blackwelder, W., Potdar, V., et al. (2021). Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, Phase 3 trial. The Lancet. 398(10317), 2173-2184
2Kim 2021 COVAXIN Safety Summary
3Lambrou AS, Shirk P, Steele MK, et al. Genomic Surveillance for SARS-CoV-2 Variants: Predominance of the Delta (B.1.617.2) and Omicron (B.1.1.529) Variants — United States, June 2021–January 2022. MMWR Morb Mortal Wkly Rep 2022;71:206–211.
4Garcia-Beltran WF, St Denis KJ, Hoelzemer A, et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2022 Feb 3;185(3):457-466.e4.
5Edara, V. V., Patel, M., & Suthar, M. S. (2022). Covaxin (BBV152) Vaccine Neutralizes SARS-CoV-2 Delta and Omicron variants. medRxiv
6World Health Organization (WHO). WHO issues emergency use listing for eighth COVID-19 vaccine. November 3, 2021. Accessed on June 28, 2022. Available at: https://www.who.int/news/item/03-11-2021-who-issues-emergency-use-listing-for-eighth-covid-19-vaccine.
7Vadrevu KM, Reddy S, Jogdand H, et al. Immunogenicity and reactogenicity of an inactivated SARSCoV-2 vaccine (BBV152) in children aged 2–18 years: interim data from an open-label, nonrandomised, age de-escalation Phase 2/3 study. The Lancet Infectious Diseases. 16 Jun 2022. https://doi.org/10.1016/S1473-3099(22)00307-3
8ClinicalTrials.gov Identifier: NCT05258669: Immuno-bridging and Broadening Study of a Whole, Inactivated COVID-19 Vaccine BBV152 in Healthy Adults.
9Centers for Disease Control and Prevention (CDC). COVID Data Tracker. April 27, 2022. Accessed on May 26, 2022. Available at: https://covid.cdc.gov/covid-data-tracker.
10Food and Drug Administration (FDA). Expanded Access | How to Submit a Request (Forms). Last Updated September 23, 2019. Accessed on May 31, 2022. Available at: https://www.fda.gov/newsevents/expanded-access/expanded-access-how-submit-request-forms