Notification to Pharmaceutical Companies: Clinical and Bioanalytical Studies Conducted by Synapse Labs Pvt. Ltd. are Unacceptable
[06/18/2024] FDA is notifying sponsors of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) that clinical and bioanalytical studies conducted by Synapse Labs Pvt. Ltd. (Synapse)—a contract research organization (CRO) based in Pune, India—are not acceptable because of data integrity concerns. Studies conducted by Synapse must be repeated.
During analyses of study data generated at Synapse and submitted in several applications, FDA identified significant unexplained anomalies in the data that indicate the data were falsified. FDA issued an initial general correspondence letter (GCL) to Synapse on February 12, 2024, outlining significant data integrity concerns for bioequivalence studies conducted by the CRO and submitted in support of ANDAs.
FDA issued a second GCL to Synapse describing the agency’s determination that study data from Synapse must be rejected. FDA is requiring sponsors of approved, tentatively approved or pending ANDAs and NDAs to repeat the bioavailability/bioequivalence studies, when those studies are essential for approval, using an entity other than Synapse or any other organization with known unresolved data integrity concerns. FDA encourages affected sponsors to contact the relevant FDA review division in the Office of Generic Drugs or the Office of New Drugs for further information or clarification.
FDA has determined that data from Synapse are not acceptable to support a determination of safety or effectiveness for brand-name drugs, or to show affected generic products are bioequivalent to brand-name products. FDA is changing the therapeutic equivalence rating to “BX” for any currently approved and marketed prescription generic drug applications that relied on data from Synapse until adequate repeat studies are submitted and determined to be adequate to demonstrate bioequivalence. A “BX” rating indicates data reviewed by the agency are insufficient to determine therapeutic equivalence (substitutability) of the generic product to its brand-name product. A drug with a “BX” rating is still approved and can be prescribed, but is not recommended as automatically substitutable at the pharmacy (or by a pharmacist) for the brand-name drug.
FDA has been investigating postmarketing safety reports for marketing applications that relied on bioavailability/bioequivalence studies conducted by Synapse for approval. To date, the agency has not identified signals related to problems with the safety or quality of the approved drugs. FDA remains vigilant and will act should we identify safety issues. Patients should not make changes to their treatment except in consultation with their health care professional.
FDA is committed to protecting the health of the American public by holding approved products to high standards of quality, safety and efficacy.
Additional information
- General Correspondence Letter Issued to Synapse
- Sample Information Request Letter to ANDA Sponsors
- Sample Information Request Letter to NDA Sponsors
Questions and Answers Regarding Data Integrity Violations at Synapse
FDA is asking companies with approved or tentatively approved abbreviated new drug applications (ANDAs) that are affected to respond within 30 days with their plans to either:
- re-conduct these studies at a site with no known unresolved data integrity concerns in order to submit an amendment or a supplement, as applicable, within the next year, or
- voluntarily request withdrawal of the affected ANDA.
FDA has changed the therapeutic equivalence (TE) rating for the affected generic products in Approved Drug Products with Therapeutic Equivalence Evaluations (commonly referred to as the Orange Book) to “BX.” This means that the data are insufficient to show that the generic products affected provide the same therapeutic effect as the brand-name product. A drug with a “BX” rating is still approved and can be prescribed but is not recommended as automatically substitutable at the pharmacy (or by a pharmacist) for the brand-name drug.
FDA is also asking companies with approved new drug applications (NDAs) that are affected to respond within 30 days with their plans to re-conduct these studies at a site other than Synapse—or any other organization with known unresolved data integrity concerns—in order to submit a supplement. Alternatively, companies may consider voluntarily withdrawing their affected NDA.
FDA has restrictions on what it can legally disclose because it is confidential information whether a particular drug applicant uses a particular contract research organization for studies it submits. However, if you are concerned about whether a generic drug you are taking has a “BX” rating, you can go to the Orange Book website and look up that drug. Type in the name of your drug and, in the list that comes up, look for the name of the manufacturer that appears on the bottle. Then look for the row with that drug and manufacturer and find the code in the column “TE Code.” If the code is “BX,” you may wish to consult with your health care provider about continued use of the drug. (Many drugs have a “BX” rating for reasons unrelated to this action, but the drugs affected by this action have, as noted, had their ratings changed to “BX.”)
You can also look up your drug in the Orange Book by the drug’s NDA or ANDA number. To find the ANDA or NDA number you will first need to find the National Drug Code (NDC) number listed on the bottle, or ask your pharmacist if this information is not available. You can enter the NDC number into the National Drug Code Directory to find the NDA or ANDA number for your drug. Once you have the NDA or ANDA number you can search the Orange Book website with that number.
A drug with a “BX” rating is still approved and can be prescribed but is not recommended as automatically substitutable at the pharmacy (or by a pharmacist) for the brand-name drug. To market a generic drug, a manufacturer must demonstrate, among other things, that its product is bioequivalent to an FDA-approved reference listed drug. Bioequivalent products are those that demonstrate a similar rate and extent of absorption of the therapeutic ingredient (the drug and/or active metabolite). Methods to establish bioequivalence vary by the type and nature of the drug. FDA publishes recommendations on how to establish bioequivalence for many drugs on FDA.gov.
Generic drugs that are pharmaceutically equivalent and have been shown to be bioequivalent to the reference listed drug generally are given a therapeutic equivalence (TE) code of therapeutically equivalent (which is reflected in a TE code starting with the letter “A”). TE codes are a standard format for representing known information about a specific generic drug. TE codes provide guidance to health care professionals regarding whether different prescription drug products are therapeutically equivalent to one another. More complete information about the coding system is on FDA’s website.
FDA continues to investigate postmarketing safety reports for marketing applications of drugs that relied on bioavailability/bioequivalence studies conducted by Synapse for approval. To date, FDA has not identified reports that raise signals of new serious safety risks with these products.
FDA monitors adverse event reports for brand-name and generic drugs. The monitoring of adverse events, including reports of therapeutic inequivalence, is one aspect of FDA’s overall effort to evaluate the safety of all drug products. Many times, reports of adverse events describe a known reaction to the active drug ingredient.
Reports are monitored and investigated, when appropriate. Complaints related to therapeutic inequivalence are carefully investigated. The investigations may lead to changes in how a product (brand-name and generic counterparts) is used or manufactured.
Patients should not make changes to their treatment except in consultation with their health care professional. If you, or those under your care, are taking any products with a therapeutic equivalence rating of “BX” and have concerns, contact the prescribing health care provider to discuss whether or not a different drug would be more appropriate.
FDA has notified Synapse that it is the company’s responsibility to develop, implement and execute corrective and preventive actions that are sufficient to ensure these and similar types of violations do not occur in future studies. For FDA to rely upon data generated by Synapse in future applications, the company will need to address these system-wide failures and ensure the company maintains compliance with FDA regulations.