As per NDCT Rules under Rule 2 (w) subclause (v) [not the sub-clause related to vaccines]“new drug”[1] means, (v), shall continue to be new drugs for a period of four years from the date of their permission granted by the Central Licencing Authority and the drugs referred to in sub-clauses (iv) and (v) shall always be deemed to be new drugs;
Its interpretation is that when 4 years elapse after grant of initial permission by Central Licencing Authority (CLA), said drug is no more recognized as “New Drug” in India. As per preceding subclauses (iv) and (v) modified or sustained release form of a drug or novel drug delivery system of any drug approved by the Central Licencing Authority and Vaccine recombinant Deoxyribonucleic Acid (r-DNA) derived product, living modified organism, monoclonal anti-body, [cell or stem cell derived product], gene therapeutic product or xenografts, continue to retain “New Drug” status.
According to “Frequently Asked Questions (FAQs) on New Drugs and Clinical Trials” accessible on CDSCO website[2] Answer (i) to Question 2 states “a new drug to be “a drug, including active pharmaceutical ingredient or phytopharmaceutical drug, which has not been used in the country to any significant extent has not been approved as safe and efficacious by Central Licencing Authority (CLA) i.e. DCG(I) with respect to its claims;”.
After the four-year period, unless the drug falls under specified categories, it ceases to be classified as a “new drug” under Indian regulations. On expiry of the four-year window, the responsibility for granting manufacturing permissions for such drugs shifts from the CLA to the State Licensing Authorities (SLAs), or State Food and Drug Administrations (FDAs).
Given India’s rapid advancement in pharmaceutical research, there is a pressing need to periodically review both the definitions of “new drug” and the procedures by which State authorities grant manufacturing permissions for drugs that have transitioned out of the “new drug” category primarily to ensure that tested, verified drugs of consistent quality are produced. This need for regulatory review is particularly acute for patent and proprietary medicines, where questions of therapeutic equivalence, product quality, and intellectual property may raise additional concerns.
The review is more important in case of patent and proprietary medicines.
According to THE DRUGS AND COSMETICS ACT AND RULES accessible on CDSCO website[3] Section 3(h)(ii) ―patent or proprietary medicine‖ means,— in relation to any other systems of medicine, a drug which is a remedy or prescription presented in a form ready for internal or external administration of human beings or animals and which is not included in the edition of the Indian Pharmacopoeia for the time being or any other Pharmacopoeia authorised in this behalf by the Central Government after consultation with the Drugs Technical Advisory Board constituted under section 5;
As clarified by Section 3(h)(ii), patent or proprietary medicines are not included in Pharmacopoeia. In simple terms these are excluded from pharmacopoeia. Consequently, their specifications and analytical procedures are not available in the public domain.
If a subsequent manufacturer—such as a generic company—seeks manufacturing authorization for a patent or proprietary medicine (PPM) after the expiration of four years from the date of the initial approval by the CLA, logically applicant must submit documentary evidence demonstrating equivalence to the CLA-approved PPM. Else it is quite possible that moiety and or composition described in subsequent application, may not be identical to the one for which initial permission was granted by Apex authority. It may lead to introduction of a moiety and or composition into the market which would be different from the one for which initial permission/s was/were granted.
Establishing such equivalence presents significant challenges, especially for complex molecules such as Complex APIs e.g. polymers or biosimilars and their formulations. Polymers exist in very wide range of molecular weight. The same polymer with different molecular weights exhibits distinct properties. In some instances, a polymer of a particular molecular weight does not possess properties present in the same polymer of a different molecular weight. Same polymer with a different molecular weight may pose risks to human health e.g. such as failure to disintegrate, or triggering allergic response or accumulation in bodily fluids, or interference with vital organ function.
Given the complexities associated with PPMs, more specifically polymers and complex molecules as well as the interpretation and application of the existing provisions of the Act and Rules, for subsequent applications for permission to manufacture complex molecules which are PPMs, several critical issues warrant careful consideration.
- Does the law mandate in positive language, documentary evidence of establishing equivalence with the initially granted moiety or composition?
- Do SLAs require documentary evidence of establishing equivalence for their evaluation, particularly when the subsequent application concerns a PPM that is a complex molecule or a polymer with a broad molecular weight distribution?
- What would happen if documentary evidence establishing equivalence with moiety initially granted, is not critically reviewed before granting subsequent manufacturing permissions to generic applicants?
- Alternatively, are SLAs granting subsequent manufacturing permissions without verifying the documentary evidence establishing equivalence with the CLA-approved APIs or drugs because it is not specifically defined by positive text of the law to that effect?
Impact of decision taken on questions stated above:
- Text of present law is silent about requirement of establishing equivalence with initially approved moiety. It provides flexibility to subsequent applicant to apply for and procure grant or permission without verifying and establishing if his moiety is identical to the one initially approved or is a variant of initially approved moiety.
- If the answer to question 2 is “no,” it possibly indicates that SLAs have not correctly interpreted the provisions concerning the grant of manufacturing permissions for subsequent applications. Specifically, failing to require documentary evidence establishing equivalence with the CLA-approved API undermines the fundamental purpose for which existing provisions were created and the responsibility was assigned to the SLAs. Granting permission under such circumstances would contravene the legal framework and defeat the purpose of creating the law. Conversely, if the answer is “yes,” this signifies the correct procedure, as it upholds the intent behind the legislative provisions that pave way for subsequent grants without slightest possibility of granting a subsequent permission for any variant of initially approved moiety.
- Wrt question 3 above, it is critical to emphasize that when evidence of equivalence is neither mandated, submitted, nor reviewed, and subsequent permissions are granted, it may result into an incident that falls well within the ambit of Section 9(b) or (c) i.e. Misbranded Drugs, OR 17A(a) or (c) or (e) or (f) OR 17(B)(b) or (d) when compared with the quality of initially granted moiety.
- Regarding question 4, a “no” response implies that the provision’s intent has been fulfilled. However, a “yes” response indicates a failure to uphold the legislative purpose of creating the provisions when moiety under discussion is PPM or otherwise. Such misinterpretation leads SLAs to erroneously grant permissions for APIs and drugs that are not, in reality, equivalent to those approved by the CLA four or more years prior.
This means SLAs may be authorizing the manufacture of APIs or drugs that differ substantially from the CLA-approved versions and have not undergone requisite evaluations for safety, toxicity, and efficacy. Essentially, this constitutes the unauthorized approval of a “new drug,” which is outside the SLA’s jurisdiction. The authority to approve the manufacture of a new drug rests solely with the CLA, following thorough safety and toxicity assessments. Consequently, when SLAs grant manufacturing permissions for APIs or drugs without substantiated equivalence to those sanctioned by the CLA, they are permitting the production of substances whose identity, purity, impurity profile, pharmacological effects, safety, and toxicity have not been adequately established and thus amounting to approval of unverified API or drug. This set of issues is especially significant when considering the regulatory oversight of complex molecules and polymers, given the profound impact that variations in molecular weight can have on safety and efficacy.
Such subsequent grants of manufacturing permission pose a significant risk to public safety and health. However, a careful and nuanced interpretation acknowledging underlying intent of the relevant provisions—attuned to the original legislative intent—can effectively mitigate this threat. Granting a permission to a moiety which is not equivalent to initially granted moiety can’t be legislative intent.
Present provisions mandate conducting BA/BE only for oral compositions if the active ingredient belongs to BCS Class II or IV. It does not take care of APIs and compositions for other routes of administration and hence creates porous ecosystem for launch of subsequent drugs.
Like PPM, mandating and verifying establishment of equivalence with moieties official in any other compendium is necessary. In today’s knowledge-driven economy, as India rapidly consolidates its position as the “pharmacy of the world,” it is both timely and imperative to review and clarify these provisions, by positive text of law, mandating specific performance and review, without giving space for subjective interpretations, not only in the interest of Public health in India but for global public health. Clearly defined law, correct interpretation and its application will better safeguard public safety, enhance the credibility of Indian health ministry and SLAs. Where an ambiguous text of the law has to be supported by foot note to indicate legislative intent.
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