Explained: Approval process to make allopathic, ayurvedic drugs in India

There have been several controversies around the efficacy of Ayurvedic medicines compared to allopathic drugs in the past two years, especially when health became the biggest topic across the world. While allopathy proved its mettle by fighting a novel virus like COVID-19, boosting immunity using traditional solutions and Ayurvedic medicines gained popularity too.

In India, flag bearers of both streams of medicine are often at loggerheads. In fact, Dr Cyriac Abby Philips, a Kerala-based hepatologist (liver specialist), recently drew ire after he, in an interview, discussed liver injuries that could occur with the use of herbs. He later tweeted that he received a letter from the Ministry of AYUSH that said he defamed Ayurvedic medicine by "calling it unscientific, hepatotoxic".

In another such controversy, in a video circulating on social media in May 2021, yoga guru Ramdev was seen claiming that allopathy is a "stupid science" and that many people died during the pandemic because of allopathic medicines instead of lack of oxygen. The Indian Medical Association later demanded action against him. The then Union Health Minister Dr Harsh Vardhan asked Ramdev to withdraw the statement and the yoga guru apologised saying he was reading out a forwarded WhatsApp message he had received.

While claims and counterclaims have been made from both sides, the debate still lacks information. FactChecker read up official documents and spoke to health experts to start introducing information to this entire discussion. The first step we have taken is to find the process of approval new medicines from both these streams undergo to be manufactured and marketed.

Approval Process for New Allopathic Medicines

The approval process of all drugs, be it allopathic, ayurvedic, siddha, or unani drugs, is governed by the Drugs and Cosmetics Act, 1940 and the Drugs and Cosmetics Rules, 1945, which were both last amended in 2016.

What's a new drug? A new drug, defined under the New Drugs and Clinical Trials Rules 2019, includes:

- a drug with an active pharmaceutical ingredient or phytopharmaceutical drug, which has not been used in the country before

- a drug approved for certain claims and proposed to be marketed with modified or new claims

- a fixed dose combination of two or more drugs, approved separately and proposed to be combined for the first time, or where the ratio of ingredients in an approved combination is proposed to be changed

- a modified or sustained release form of a drug or novel drug delivery system of any approved drug

- a vaccine, recombinant Deoxyribonucleic Acid (r-DNA) derived product, living modified organism, monoclonal antibody, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug

STEP 1: For manufacture or import of a new drug for sale or to undertake clinical trials in India, a pharmaceutical company needs to apply for permission with the Central Drugs Standard Control Organisation (CDSCO). This requires the applicant to fill Form 44 or the application form, deposit Rs 50,000 and submit supporting data, like information on active ingredients of the drug, drug's generic and chemical names, physicochemical data, analytical data, stability studies, data on formulation, animal pharmacology data, animal toxicology data, human clinical pharmacology data, regulatory status in other countries, full prescribing information and complete testing protocol.

Form 44 can be accessed and submitted through SUGAM, an e-governance portal for CDSCO. Through SUGAM, applicants can apply for No Objection Certificates, licenses, registration certificates, permissions, and approvals.

"When an applicant seeks permission to do clinical trials, they need to present lab data based on testing of the drug on mice, rabbits, dogs and monkeys," Murali Neelakantan, principal lawyer, Amicus, and former global general counsel, Cipla. Permission has to also be sought for such lab trials.

"Once the approval for clinical trials is received, permission to manufacture the drugs which would be utilised for the clinical trials will be necessary," added Neelakantan.

If a company wishes to import or manufacture a fixed dose combination of two or more drugs, it should fill Form 44 and deposit a fee of Rs 15,000 with the supporting data.

STEP 2: Before moving on to clinical trials, an ethics committee has to be formed that has to ensure the protection of the rights and safety of the human subjects involved in the trial. The committee is also responsible for reviewing and approving the protocol, the suitability of the investigators, facilities, methods and adequacy of information and confidentiality safeguards. It has medical, scientific, non-medical and non-scientific members.

An Ethics Committee must apply for registration with the licensing authority. Once registered, it should review and accord its approval to a clinical trial and also carry ongoing review of the trial on intervals.

STEP 3: This step is to prove the drug's safety and efficacy for the Indian population: Clinical trials. Trials can only be initiated at the site approved by the licensing authority.

New drugs discovered in India require clinical trials to be carried out in India from Phase I, according to the Drugs and Cosmetics Rules, 1945. Whereas, for new drug substances discovered in other countries, the Phase I (human trials) data of clinical trials generated outside India can be submitted. This can get the company permission to repeat Phase I trials or move on to Phase II (exploratory clinical trials) trials and subsequently Phase III (confirmatory clinical trials) trials concurrently with other global trials for that drug. Clinical trials may be waived if new drugs approved in other countries have been in use there for several years.

Applicants must take permissions for each phase of the clinical trials separately. So, the performance of the previous phase affects the approval for the next one.

According to CDSCO's approval process, after the submission of the application along with the prescribed fees, a preliminary evaluation is done to check for completion. In addition to the protocol regarding clinical trials, for certain classes of generic drugs to be manufactured in India, the applicants also need to seek permission to conduct Bioequivalence (BE) of a drug product. The CDSCO mentions that the BE of a drug product is "achieved if its extent and rate of absorption are not statistically significantly different from those of the reference product when administered at the same molar dose".

"Very often bioequivalence studies may be sufficient if just the dosage form is changed. For example, an existing drug is changed from a pill to a capsule. It just needs to be shown that the proposed form of the drug has the same effect. A full clinical trial may not be necessary," Neelakantan added.

The Subject Expert Committee then reviews the permission applications and the data generated through clinical trials or BE studies, the chemistry & manufacturing control data, which details the manufacturing process of the drug, is reviewed too. "This essentially needs to be submitted for all drugs. The raw materials used, the standards of raw materials, quality assurance and control tests are integral to the process," explained Neelakantan.

An on-site facility inspection is also carried out before the final approval. If all the data is satisfactory and approved, the company, depending on the application, gets final approval to manufacture the new drug formulation.

Approval Process for Ayurvedic, Unani and Siddha Drugs

According to the World Health Organization's Global Report on Traditional and Complementary Medicine 2019, there was a consistent increase in the number of countries framing national policies on traditional medicines. "The number of countries having a national policy on traditional and complementary medicine almost doubled between 1999 and 2005, and then doubled again between 2005 and 2018. By 2018, a total of 98 countries, more than 50% of the 194 member states, had such a national policy," read the report.

Two types of medicines are manufactured under Ayurveda, Siddha, and Unani drugs: One are the text-based classical medicines and the other are patented or proprietary drugs.

Classical Medicines: The text-based medicines include all medicines which are manufactured "exclusively in accordance with the formulae described in the authoritative books of Ayurvedic, Siddha and Unani Tibb system of medicine," reads the Drugs and Cosmetics Act, 1940, which has a comprehensive list of 54 Ayurvedic texts, 31 Siddha texts, and 14 Unani Tibb texts.

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Every state government appoints a licencing authority to approve such drugs. To seek a licence to manufacture the drugs, Form 24-D is to be filled and submitted to the authority.

The General Guidelines For Safety/Toxicity Evaluation Of Ayurvedic Formulations followed to apply and acquire a licence to manufacture a drug are based on the ingredients used in the medicine. When it comes to the approval process, Ayurvedic, Siddha and Unani text-based classical drugs are divided in three categories: if the applicant seeks to use the drug to treat the same disease as mentioned in the text, wants to alter the dosage and wants to treat another ailment. For the first two kinds of applications, no safety study or proof of effectiveness are required. For the last one, no safety study is needed, but a proof of effectiveness and published literature on the drug have to be submitted.

"The use of the drug should match with that mentioned in the text. If it does not, a trial is necessary. For example, if an applicant says that a medicine, which is proven to be an immunity booster, will be used to help breast cancer patients, a clinical trial would be needed," said Dr Omkar Kulkarni, head of formulation development of Charak Pharma Pvt Ltd.

Patent or Proprietary Drugs: The Act defines patented or proprietary Ayurveda, Siddha, and Unani medicines as those which contain ingredients mentioned in the formulae of the respective authoritative books, and does not include a medicine administered by parenteral route (through injections, syringes, catheters).

For approval, patent or proprietary medicines (PPM) have two categories: medicines that have ingredients listed in classical texts and those that have ingredients listed in the Drugs and Cosmetic Rules, 1945, which is essentially a list of "poisonous substances under the Ayurvedic (including Siddha) and Unani Systems of Medicine".

For the first category, no safety study is required but published literature and proof of effectiveness based on pilot study should be provided, according to General Guidelines For Clinical Evaluation of Ayurvedic Interventions. For the second category, a safety study, published literature and proof of effectiveness all are required. "For such substances, 'Caution: to be taken under medical supervision' is to be conspicuously labelled on the container," said Kiren Rijjiu, the then Minister of State for the Ministry of Ayurveda, Yoga & Naturopathy, Unani, Siddha & Homeopathy, in a response to the Lok Sabha on March 12, 2021.

"For drugs that are listed in the recognised texts, there's no need for trials because the ingredients are already approved. And basically, a pilot study is a small trial done on fewer participants [when compared to a clinical trial]," Gayatri Gaonkanr, Assistant Professor at Ras Shastra & Bhaishajya Kalpana department in Mumbai's RA Podar Ayurved Medical College, told FactChecker.

"Unless it is a new formulation, clinical trials are not necessary. Medicines approved by individual state authorities are sold throughout the country," she added. In February 2019, The Hindu reported, Kerala withdrew its order that made clinical trials mandatory and so no new Ayurvedic drugs can be introduced in the state without the long-drawn process of trials and studies.

"There are two types of licences: state and central. If a firm wants to manufacture and sell in a particular state, then a state licence is enough, which also falls under the Union AYUSH Ministry. And, if they want to sell in other states or on an online platform, then a central licence is required too," explained Dr Kulkarni.

All clinical trials, be it for new allopathic or ayurvedic drugs, can be registered on the Clinical Trials Registry - India (CTRI), a public record system for registration of clinical trials. For allopathy, clinical trials are to be carried out after receiving permission to conduct the trials and development of integrated protocols for them. On the other hand, for Ayurvedic, Siddha and Unani medicines, according to the General Guidelines for Clinical Evaluation of Ayurvedic Interventions, the preliminary/pilot studies, pre-clinical assessment on safety and toxicity, quality assurance and standardisation of trial drugs must be documented before a clinical trial is undertaken.

"Clinical trials for ayurvedic medicines don't happen phase-wise like for allopathic drugs. Only one clinical trial and a safety study are required. If the medicine is a new clinical entity, then only different phases of clinical trials are necessary," Dr Kulkarni told FactChecker.

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Submission Data: The data to be submitted along with the application to conduct clinical trials or import or manufacture Ayurvedic drugs includes botanical name of the plant, published literature on the plant, product, or drug, side-effects on current usage, published scientific reports, pharmacodynamic information and monographs.

Additionally, the applicant needs to add information they generated including identification, authentication and source of the plant used for extraction and fractionation, process of extraction and subsequent fractionation and purification, formulation of the drug, Manufacturing process, stability data, safety and pharmacological information, human studies including clinical trials, regulatory status and marketing information.

"A new herb will need to be approved. For example, if one gets an Australian herb, which is not mentioned in the Ayurveda text, then it may not get approved and you'd have to get a food and safety licence for it," mentioned Dr Kulkarni.

Any applicant seeking a licence or renewal of licence to manufacture Ayurveda, Siddha, and Unani medicines must submit real-time stability studies of the medicine specifying its shelf life, according to the Ayurvedic Pharmacopoeia of India. The drug manufacturing unit must follow the Good Manufacturing Practices and it has to be manufactured under the supervision of competent technical staff. Based on satisfactory performance on these standards, the State Licencing Authorities can provide a licence to the applicant.

In fact, the Ministry of AYUSH, on April 2, 2021, directed all state licensing authorities to complete the approval process and dispose of applications of manufacturers within a week if the prescribed standards and relevant provisions of the Drugs & Cosmetics Rules, 1945 are fulfilled.