In light of the executive order waiving the requirement to conduct clinical trials for new drugs approved in a few selected jurisdictions, we are pleased to bring to you this guest post by Md. Sabeeh Ahmad, discussing the implications of this executive order. Sabeeh is an Advocate and is a law graduate from AMU, Aligarh. His previous posts can be accessed here.
Of Clinical Trial Waivers in India: The Misses Outweigh the Hits
By Md. Sabeeh Ahmad
The Drug Controller General of India (DCGI) on August 7 via an executive order waived the requirement of local clinical trial for approval of “new drugs” if they are approved in the US, UK, Japan, Australia, Canada, and EU. The DCGI used Rule 101 of the New Drugs and Clinical Trials Rules, 2019, which allows it to approve new drugs without local trials. The categories of drugs that may be considered have also been specified – orphan drugs for rare disease, gene and cellular therapy products, new drugs used in pandemic situations, new drugs used for special defence purposes and new drugs having significant therapeutic advances over the current standard care.
New Drugs and the Existing Regulatory Process
The New Drugs and Clinical Trial Rules 2019 define the New Drug as (i) An active pharmaceutical ingredient or phytopharmaceutical drug, not approved as safe and efficacious by the Drugs Controller General (India) for its claims (ii) A drug marketed in India for certain claims, now to be marketed with certain new claims, indication, route of administration, dosage, and dosage form (iii) Two or more drugs in a fixed combination.
For approval in India, the entire process is laid down in 4 phases. As laid down in 3(2) of the First Schedule, New Drugs and Clinical Trial Rules 2019:
Phase I requires conduct of clinical trials after the approval from the central licensing authority to do so. The Central Licencing Authority after scrutiny of the information and documents furnished may give a go ahead to proceed towards the clinical trial. The objective is to estimate safety and tolerability with the initial administration of an investigational new drug into humans
Phase II trials are to evaluate the effectiveness of a drug for a particular indication or indications in patients with the condition under study and to determine the common short-term side-effects and risks associated with the drug.
Phase III studies primarily focus on demonstration or confirmation of therapeutic benefits confirming the preliminary evidence accumulated in Phase II. For new drugs approved outside India, Phase III studies may need to be carried out if scientifically and ethically justified, primarily to generate evidence of efficacy and safety of the drug in Indian patients. In case of an application of a new drug already approved and marketed in other country, where local clinical trials in India are waived off or not found scientifically justified for its approval for manufacturing for the first time in the country, the bioequivalence studies of such drug is required to be carried out.
Phase IV or post marketing trials of new drugs are performed after the approval of the drug and includes additional drug-drug interaction, dose response or safety studies.
Concerns with the Waiver
The primary concern with respect to non-conduct of clinical trials in India is its genetic diversity. The Parliamentary Standing Committee on Health had back in 2012 noted that testing drugs in the Indian ethnic groups was of “paramount importance” before approving any drug of foreign origin (Prashant Reddy had covered it here). The report had emphasised that the effect of drugs vary with various ethnic groups. The report had also found glaring shortcomings with the 39 foreign origin drugs it had analysed which included non-conduction of Phase III trials (in 28% drugs), non-fulfilment of clinical trials on 100 patients (2 drugs), opinion of medically qualified experts not obtained (in 64% drugs), and no permission for sale in major developed countries (33% drugs), amongst others. Subsequently, the Prof. Ranjit Roy Chaudhury Expert Committee had also flagged the need for studies on different ethnic groups for foreign approved drugs, and if studies showed significant ethnic variations in studies, then it considered it imperative that the trial be done on the Indian population and in different regions of India. To emphasise more on the clinical trials on a diverse ethnic population – around 20% of the drugs approved in recent years in the US have had differential outcomes based on ethnicity. Take for example Warfarin, (used to treat and prevent blood clots) which is required in higher doses for Caucasians than African-Americans.
The second concern (more of a bargain of sorts) is the lack of reciprocity for Indian manufactured/approved drugs in foreign countries. Although India’s drug manufacturers have had a seriously problematic history with respect to quality (read here, here, and here), India is now considered a preferred and untapped hotspot for clinical trials given its genetic diversity amongst other reasons (read here, here and here). With the waive off, foreign pharmaceutical companies may enjoy a significant dominant position as against their Indian counterparts in their ease to access the Indian market. But at the same time, it cannot be emphasised more that if India does want to maintain the “pharmacy of the world” tag, recover from its fall from grace owing to multiple instances of serious quality concerns, and demand reciprocity, it does need to introspect the drug quality system, match stringent international standard, instead of just “managing”. The US is in fact considering a drug reciprocity bill (which will allow for reciprocal approval of drugs, devices and biologics from foreign sponsors in certain trusted, developed countries) since 2015, which unsurprisingly, does not have India amongst the list of countries, although Indian companies did supply 47% of all “generic” prescriptions filed in the US.
High cost of clinical trials has been commonly argued as the reason for high drug pricing by pharmaceutical companies. But since 2015, especially in the US, the FDA has begun providing data on clinical trials. As compared to earlier data, the number of people actually signing up for clinical trials seem to have gone down drastically, or better said, we now have actual data without inflating costs of developing new medicine. For example, in 2003, a study stated that clinical trials accounted for more than 58% of costs in developing a new drug – an average of 5303 people enrolled for approval of a new drug. Fast forward 2018, the FDA reported that for priority drugs, the median enrollment in 2018 was only 318 patients. For orphan drugs, only 229. Clinical trials, therefore, were not be blamed anyway for high cost of drugs, and also with their waiver in India, do we assume that the pricing for such drugs would be reasonable now?
To my understanding, the waiver can be interpreted as pedestalizing the approval processes in the aforesaid developed countries. However, several concerns lie within their processes as well. For example, 40% of anti-cancer therapies approved through the US FDA’s accelerated approvals pathway between 2013 and 2017 didn’t show clinical benefit in follow-up trials, leading to questions of the actual efficacy of drugs. For a more relatable drug, readers will recall Remdesivir, approved for use against COVID-19 in 2020. Reports had immediately surfaced against the clinical trials and effectiveness of Remdesivir.
As for rare diseases (one of the categories approved in India for clinical waiver), the US FDA runs a specified Accelerating Rare disease Cures (ARC) Program. This accelerated approval process by the FDA has been under scrutiny for uncertain efficacy and high costs amongst other issues. Given the issues drug approvals face in countries like the US itself, it is not incorrect to infer that a direct waiver of clinical trials seems to be not the best mode of action.
Positives, If Any?
The clinical waiver seems to be an advantage if we direct our focus on the drug lag for new drugs in India. A drug lag precludes Indian patients from accessing new medicines at the same time as they are approved elsewhere. The relative drug lag for the CDSCO vis-a-vis the US FDA, EMA (EU), and PMDA (Japan) was 43.2 , 25.6 , and 30.3 months, respectively. The delay in introduction can be a worrying trend for Indian patients and the waiver may turn out to be a deterrent for the drug lag. Drugs like Zolgensma (for spinal muscular atrophy) and QDenga (dengue vaccine) have been delayed in India due to the requirement of bridging studies. Japan, in order to tackle its drug lag, had in December, 2023, also introduced a waiver of the requirement for domestic phase I clinical trials of drugs developed overseas.
Conclusion
Keeping in mind that drug lag is an issue that affects access to potential life-saving medicines in India, the concerns of a waiver in clinical trials are well-founded. Over-reliance on developed country approvals may not be the best bet to make when it comes to drugs. Other than that, the central argument remains that of safety and efficacy of such drugs without local trials on a genetically diverse population. India is home to at least six ethnic groups (Negrito, Australoid, Mongoloids, Dravidian, Western Brachycephals, and Nordic Aryans/Caucasians) and with such difference in ethnicity comes a challenge of different outcomes for drugs and their impacts. We may play the odds and assume that the drugs green flagged for waiver of clinical trials may work as efficiently as they may have worked in developed countries, but the odds may not always be in our favour. And with drug categories such as that of rare diseases and pandemic situations, the primary question that looms is – if we are willing to risk it all?