Drug submissions: Procedures to reach regulatory approval

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Before a new drug or biologic can go to market, a drug submission must be compiled and filed with all relevant regulatory agencies to seek a review and, ultimately, regulatory approval.

Canada, the US and the EU each require different types of drug submissions (Table 1^1-4 ).

Table 1: Drug submission types: Canada, the US and the EU

Canada	New Drug Submission (NDS)―for both drugs and biologics
US	New Drug Application (NDA)―for drugs Niologic License Application (BLA)―for biologics
EU	Marketing Authorization Application (MAA)―via the centralized procedure for eligible products (Table 24). For other products, routes such as the decentralized procedure, the mutual recognization procedure or national authorization apply.

Table 2: EU: Products eligible for the centralized procedure

Mandatory

Optional

Human medicines for the treatment of HIV/AIDS, cancer, diabetes, neurodegenerative diseases, autoimmune and other immune dysfunctions, and viral diseases Medicines derived from biotechnology processes, such as genetic engineering Advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines Officially-designated “orphan medicines”(medicines used for rare human diseases)

Other new active substances not authorized in the European Community before May 20, 2004 Medicinal products that contribute significant therapeutic, scientific or technical innovation or are in the interests of patient health A generic copy of a centrally authorized product

Review and approval procedures for drug submissions

Each jurisdiction has its own procedures to review drug submissions filed to their regulatory agency. These procedures can vary substantially with respect to how the drug submission will be handled, the composition of the review team, review timelines and so on.^1-4

Despite the differences, the procedures to reach regulatory approval generally follow these stages:

Pre-submission meeting

Although optional, a pre-submission meeting⁵ is often useful so that any scientific or submission issues can be discussed and resolved prior to the actual submission. This meeting also provides the agency insight into your drug or biologic submission and allows them to organize their internal resources accordingly.

Tip: Ensure the issues discussed are addressed in the submission dossier, with additional data or a sound scientific justification provided.

Pre-submission activities

Review what communication is required prior to submitting your marketing application. In Canada, sponsors (that is, applicants) are requested to send advance requests for Priority Review status and for Requests for Advance Consideration under the NOC/c.⁶ In the EU, an applicant should notify the European Medicines Agency (EMA) of its intention to submit via the centralized procedure at least seven months before the drug submission.⁷ Any orphan drug designation should also be requested and approved before your drug submission will be reviewed as an orphan product.

Administrative review

Once a drug submission is filed, it goes through an administrative review to ensure its acceptability (for example, completeness). A submission number (such as NDS Control Number or NDA number) is assigned and this number must be used in all subsequent communication with the regulatory agency.

If the drug submission is found to be acceptable at this stage, it will be accepted for review. If minor deficiencies are identified (for example, missing forms), the agency will normally allow the sponsor time to respond. If the response is satisfactory, then the submission will proceed to review. If the sponsor fails to provide the requested information within the set timeframe, or if that the response is unsatisfactory, the agency can reject (refuse to file) the submission.

Tip: Adhere to the response timeline indicated. Should you need more time, contact the agency and request an extension, providing a justification. The agency will determine if an extension can be granted.

Agency review and sponsor response

Once a drug submission is accepted, it is evaluated by reviewers with the necessary expertise. In the US, for example, a review team may include clinicians, pharmacokineticists, pharmacologists, toxicologists, statisticians, microbiologists and chemists, as well as a regulatory project manager (RPM). The objective of the review is to confirm and validate the sponsor’s conclusion that the drug is safe and effective for its proposed use.

Once the technical review is complete, an evaluation report will be generated. If the submission is deemed acceptable, then the technical review of the submission is complete. If deficiencies are identified, then the agency will issue a list of questions for the sponsor to address within a set timeline.

This review also evaluates the text in the proposed labelling, which needs to be justified by the data submitted in the submission. If the reviewers question the proposed labelling, they will discuss revised wording with the sponsor.

Tip: Assemble a response team that can address agency questions and requests for additional information. A quick response by the sponsor facilitates the review process.

Activities prior to the agency’s decision

These may include any necessarypre-approval inspections (for example, of drug manufacturing sites or clinical trial sites). In the US, for example, the Food and Drug Administration (FDA) may decide to convene an advisory committee (AC) meeting and seek input. Based on the discussions at the AC meeting and its recommendations, the FDA may ask for additional data or analyses to review.

Decision

The decision made at the end of the review process normally results in regulatory approval, an approval with conditions, or a rejection.
*NOC/c = Notice of Compliance with conditions

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Summary: You must follow a drug submission and regulatory approval process with all relevant agencies before you can market a new drug or biologic; Canada, the US and the EU have different drug submission requirements.

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Disclaimer

The information presented in these articles is intended to outline the general processes, principles and concepts of the healthcare product development lifecycle. Since regulatory requirements are ever-changing, it is current only as of the date of publication and not intended to provide detailed instructions for product development. Every healthcare product is unique and therefore so is its associated product development lifecycle. Specific advice should be sought from a qualified healthcare or other appropriate professional.
Published: October 17, 2012

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References

1. Health Canada. (2011, March 29). Guidance for industry: Management of drug submissions. Retrieved July 18, 2012, from http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/mgmt-gest/mands_gespd-eng.php#a5.2.
2. U.S. Food and Drug Administration. (2005, April). Guidance for Review Staff and Industry. Good Review Management Principles and Practices for PDUFA Products. Retrieved July 18, 2012, from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079748.pdf.
3. European Commission. (2007, February). Notice to applicants. Volume 2A. Procedures for marketing authorisation. Chapter 2 Mutual Recognition. Retrieved July 18, 2012, fromhttp://ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap2_2007-02_en.pdf.
4. European Commission. (2006, April). Notice to applicants. Volume 2A. Procedures for marketing authorisation. Chapter 4 Centralized Procedure. Retrieved July 18, 2012, from http://ec.europa.eu/health/files/eudralex/vol-2/a/chap4rev200604_en.pdf.
5. Grignolo, A. (2008). Meeting with the FDA. In Pisano, D.J. & Mantus, D.S. (Eds.) FDA regulatory affairs: A guide for prescription drugs, medical devices, and biologics (2nd ed., pp.109-23). New York: Informa Healthcare.
6. Health Canada. (2012, July 7). Priority Review of Drug Submissions Policy. Retrieved September 26, 2012, from http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/pol/prds_tppd_pol-eng.php.
7. European Medicines Agency. (2012, April). European Medicines Agency pre-authorisation procedural advice for users of the centralised procedure. Retrieved September 26, 2012, from http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004069.pdf.