Safe, Affordable and Made-in-India. Can We Deliver?
Conversation between Mr K.M. Gopakumar (KMG), Dr Yogesh Jain (YJ) and Professor T Sundararaman (TS).
TS: Thanks Gopa and Yogesh for coming in for this conversation. We are limiting this conversation to quality, safety and efficacy of medicines that are made in India. We are not going into many other important issues like pricing, procurement, rational use, innovation, patents etc, except where it impinges on this issue. We are taking up this issue because the media is awash repeatedly with stories of poor quality of medicines from India, in exports to US, to other third world countries and also within the private market in India, and on occasion within the public sector has well. We want to understand what is the problem and why the government has not been able to fix it. This topic is also in the news in the global context because it has come up in WHO executive board meeting under the title of substandard and falsified medicines. Perhaps we could start with understanding the terms in use…
KMG: Thank you for taking this initiative. At the outset, I would like to make two statements. First, it’s important whenever we discuss any issues related to quality of medicines, we understand the politics of regulation. The term regulatory science gives the impression that it is all a science-based approach with the only purpose being of ensuring the quality of health products. But beneath this is the use of regulatory frameworks to manage competition to maintain competitive advantage. And this hidden function of medicine regulation is often overlooked.
To give an example. Regulations could require a generic manufacturer to present Bio-equivalence (BE) and Bioavailability (BA) studies which requires a comparison between the generic and the originator drug- which means double the sampling size. But the BE/BA data of the originator drug is already with regulators and could have been made available. It would have been enough for regulators to ask that the generic provide evidence that BA /BE values are within the range of the originator. But this data is kept like a trade secret and not made available, which favours the monopoly of the originator. Similarly, we need to ask why when we have generics for most medicines, we do not have generics in vaccines. For the biotherapeutic class of medicines, the regulators demand a complete comparative clinical trial to approve a biosimilar. According to the current regulatory framework the point of departure for a biologic is that, any deviation from the originator’ manufacturing process has safety and efficacy implications and therefore the non-originator producer has the burden of proving the safety and efficacy of the product Since the originator’s manufacturing process is kept as a trade secret the non-originator ends up repeating of the entire clinical trial, though all the data is with the regulatory agency.
Second, it is important to understand who and how these regulations are made, de facto and de jure. By and large, this is done by an organization called the International Conference on Harmonization ICH) which was originally established by associations of research-based companies of the USA, Japan, EU, along with the regulatory agencies of these three countries. In addition to these six founding members are three observers: World Health Organization (WHO), IFPMA (International Federation of Pharmaceutical Manufacturing Association), Canada and Switzerland. Among these members, only the six founding members had voting rights. Now they have expanded, and they included a few more developing countries. They call it as an organizing committee. But still, neither Indian associations nor the government are members. When the industry is sitting in the decision-making capacity, there are always conflicts of interests. Most of the ICH regulations have been imported as global drug quality requirement through the WHO. A WHO Meeting report published in 2002, underlined the adverse impacts of transposing ICH regulations on developing countries in terms of the costs of compliance and access to essential medicines.
It states: “The public health implications of the application of guidelines of greater technical complexity in developing countries may be far-reaching. In many countries, essential drugs required for the prevention and treatment of locally endemic conditions are not supplied by the major multinationals but by local industry or by generic manufacturers. If these supplies are unable to meet what may be unsubstantiated quality standards, the adverse impact of the withdrawal of the e drugs on the health of the population might well be far more dramatic than that of any hypothetical risk posed by failing to achieve the ICH standards.
Therefore, it is important to keep in mind that the regulatory system needs to be based on scientific evidence and mindful of affordable access to quality medicine. In this regard, the Regulatory system should strive to minimise the misuse of the system to manage competition. Often regulatory process ignores the affordable access and keeps on setting so-called gold standards without looking at the scientific evidence.
It is against this background, that we should discuss this issue of quality.
TS: Coming to the terms and definitions….:
Many terms have been used- these include substandard, spurious, falsely labeled, falsified, counterfeit medical products and so on. But from 2016 onwards, WHO has moved dropped the use of “counterfeit” and “spurious” to refer to quality compromised medicines and now uses only two words: substandard and falsified. Generally speaking, substandard means any medicine which deviates from the standard specifications and falsified is a term to refer to medicines produced without a license or without authorization. The term counterfeit is often wrongly applied to describe quality-compromised medicine. The term counterfeit should be limited to refer trademark violations when one manufacturer produces the exact copy and labels it as manufactured by another more reputed company. This definition is given in the TRIPS Agreement[i].
The term spurious, implying a so-called medicine which does not have the ingredient it claims to have, is a term used in India’s Drugs and Cosmetics Act, but it has no more in use at the international level. Drugs and Cosmetics Act 1940 uses the following terms: “, misbranded”, “spurious” and “adulterated”.
All substandard medicines pose a health problem- but they do not pose the same level of threat to patients’ safety. Regulatory authorities classify deviations as minor, major and critical. Minor deviations, like labelling not meeting some requirements, are communicated with companies having to self-correct. Major and critical deviations would require the recall of drugs and more severe action like prosecution. When reporting, it is important to denote this break-up, so as to focus on issues where action is essential and urgent and not create confusion around the rest.
Falsified medicine is an issue because the whole regulatory framework is based on the track and trace mechanism. It should be possible for a regulator to track and trace the entire process, from production, and storage in a warehouse, through transport, to retail supply- and for each step and each actor there are quality certification and license requirements. But when someone’s producing and marketing a medicine without an authorisation/license this cannot be done. The data on what proportion is substandard and what proportion is falsified is not available in the public domain, though WHO should have this information.
[i] The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) defines counterfeit trademark goods as follows:” shall mean any goods, including packaging, bearing without authorization a trademark which is identical to the trademark validly registered in respect of such goods, or which cannot be distinguished in its essential aspects from such a trademark, and which thereby infringes the rights of the owner of the trademark in question under the law of the country of importation;”
YJ: This is very useful. Before getting into the issues that have grabbed media attention, can you first describe what are the drug regulatory mechanisms in the country?
KMG: In India, we have a two-tier regulatory system. At the centre the main institutions is the Central Drugs Standard Control Organisation (CDSCO) which specifies the standards; provides marketing approval for new medicines, regulates clinical trials and controls the quality of imported drugs in the country. However, as far as local manufacturing is concerned CDSCO’s approval is the marketing approval for the first four years and the state drug control authorities are in charge of providing the manufacturing licenses for a medicine. There are no marketing approvals required after the first four years of any drug being introduced in the Indian market through local production. It means a manufacturer having obtained a manufacturing license from a state regulatory agency can market the medicine in any state. -And any trader can source the drug from any state and market anywhere else in the country. State authorities are required to draw samples from retail for quality testing and periodically inspect manufacturing units for compliance and renewal of manufacturing approvals.
If you look at the resources deployed to do the above tasks, they are completely unmatched. The number of inspectors on the field and the number of inspections don’t even cover half the requirements. Similarly, manufacturing unit inspections are also far behind norms. Business models also contribute to the current scenario. For instance, There are not any effective onsite inspection and certification processes for imported bulk drugs /active pharmaceutical ingredients that go into domestic drug manufacture.
However, the good news is that most pharmaceutical manufacturing in India largely occurs in clusters. Therefore regulatory authorities can carry out effective quality checks at the point of production even with limited resources, provided the administrative will is there.
Another business model which has implications for quality control is the practice of contract manufacturing. The manufacturer produces the medicines for one or more marketing firms who then brand, price and sell the same drug under different names. We do not have effective provisions to hold these multiple actors accountable if any mishap happens. We also know of instances where leading companies are having two facilities, one for medicines for the US with USFDA (US Food and Drug Administration approval) and another for domestic markets which have little oversight.
But we must place the whole discussion about gaps in perspective. Though we have a lot of reports of poor quality, many of which are true, it is also a fact that India still has the largest number of USFDA approved plants. And we do export a large proportion to the USA- which means we know how to get it right. Also, that regulation is always a work in progress. Even in US, there were around about 45 product recalls last year itself including voluntary recalls So quality gaps happen, but the robustness of the system is that each time you find out what went wrong and accordingly, you fix the system. Much like aircraft accident investigations, which have improved regulation and air safety. It is not that you build a system, and that’s it, it’s going to work. No, you have to be on your toes all the time and keep on improving, That’s the way the regulatory system should work.
YJ. There are three broad jurisdictions where we are worried about quality assurance in medicines. One is in the private markets within India, the other is public procurement for supply in public services. The third, where there is considerable media attention, is exported Indian medicines of poor quality leading to deaths in other low- or middle-income countries (LMICs) in Africa, Central and South Asia. Could we discuss the third? There was a report of child deaths in Gambia due to cough syrups which had a harmful adulteration of polypropylene glycol, a safe excipient, with diethylene glycol, a drug which harms the kidneys instead. The manufacturer and suppliers were identified and some action was taken. But frankly, that is not enough. What do you think are the systems’ gap and the systems corrective that should be called for?
KMG: The full investigation is yet to be put up in the public domain. But from media reports, as you said, it is excipient. One requirement is therefore that the input source, and licensing of the input ingredients should also be within the track and trace mechanism. This may create constraints on “ease of doing business” so to speak, but it is very important from a regulatory perspective. Otherwise, with manufacturers trying to cut costs in a very competitive market, it is a race to the bottom, with substandard ingredients being procured, only because they are cheaper. Only APIs from certified plants can be used.
Second, amplifying what Yogesh says, post-licensing of a manufacturer, the system of periodic reviews and re-licensing is essential and this is a state drug authority function. Currently, such reviews are non-functional or on sufficient scale. After the initial approval, the company is on auto-pilot/self-regulation and this is just not enough. And, of course, post-licensing inspections needs resources, the political will and systems that protect from political interference.
TS: I think irrespective of whether the government certifies the APIs, it is also the accountability of the manufacturer to ensure that APIs used are of sufficient quality. I also think that the system you outline, while adequate to ensure quality in medicines in the private domestic market, may not be enough for export of drugs. Here the legal position seems to be that this is the responsibility of the importing country, much like CDSCO certifies quality of drugs imported into India. High income countries are well equipped to play this role as exemplified by the USFDAs checks over quality in Indian manufacture. But countries like Uzbekistan or Gambia, from where the problems are reported may not have the systems in place. Is there any accountability for regulatory authorities in India to prevent drug exports of poor quality? Can we do something about it? Officials in India and another regional country told me that officials from countries with weak, less trust-worthy systems strike non-transparent deals with a few companies with lax standards, and when this blows up, it is the reputation of the entire Indian manufacturing sector that is under threat. More so because there are lobbies for Big Pharma who are quick to take advantage and to equate cheaper drugs with poor quality.
KMG: There are countries like Switzerland, where the regulator does not have any kind of regulation on the export part of the production. We too do not have a special regulation for the export. But in India, since you cannot produce any product just for export, without a manufacturing license or a marketing approval, this regulation for domestic consumption automatically also cover exports. Further Section 94 of the Drugs and Cosmetics Act allows exports only if “each consignment of export shall be accompanied with requisite import license from the importing country”.
But I agree that India has to go beyond this position and take proactive steps to ensure the quality of exported medicines. Two reasons. First, we ourselves project as the ‘pharmacy of the world’ and a champion of providing medicines at affordable prices, and second, many developing countries are depending upon Indian medicines, that too from mid -level companies. Legally speaking, it’s fine. I can say that, “look, I have nothing to do with it. Your own regulators came and approved it, and the medicine is sent by them to that country.” But that stand will not help because, other than these two reasons, India also gets ‘soft power’ from its solidarity with developing nations, in that our interests are not only commercial but also public health. So, India has to go the extra mile, and be proactive in fixing this problem. Also, because otherwise, this can be used to push back on generic medicines and this will only benefit multinational corporations, who would be the happiest people if there is government inaction on this front.
One vehicle for quality assurance in exports is the WHO certification scheme on the quality of pharmaceutical products moving in international commerce. This calls for all export-imports to be reported on the portal, and this report would also include a certificate from a certifying authority. In case of doubts regarding status or validity or certification or complaints the competent authority in the importing country should request a copy directly from the certifying authority, as provided for under section 4.9 of the guidelines. One notes that the authority for many India states is given in the web-document, but also some states with large manufacturing clusters are missing. Currently this is poorly functional, but this would be a good place to begin for CDSCO, in partnership with state drug authorities, for ensuring quality assurance and preventing deals with sub-standard firms. This mechanism would empower both exporting and importing countries to set this issue right.
YJ: So, moving away from economics and exports and larger national and global concerns, I want to come in now as a public health practitioner. My worry is that because of media reports of poor quality of some medicines, public trust in regulatory agencies is undermined, and all generic drugs are perceived as being of unassured quality and as a corollary, branded drugs of MNCs, become the first option. But this public perception is seriously off track. As a practitioner however, I know that generic drugs come at 1/10 the price or even less and that makes for greater access and affordability of healthcare. And I also know that many drug manufacturers are also selling the same product as generic and as branded. So how would you take on this question? Because I’m really worried about this paint brush of labelling all generics as bad.
KMG: I am afraid that the lack of systems in place to address these issues will eventually lead to a tirade against the affordable availability of generics. This also becomes convenient for the top few companies to show small players or the mid-level players in the poor light. It is important that public health practitioners, civil society, and academics demystify the relationship of quality to generics and brands.
There is in fact no evidence that branded drugs are of better quality than generics. Since there is no evidence, this belief that branded drugs are better is more an article of faith, because there is no way of knowing the quality by just seeing a medicine in the absence of some physical damage having quality implications.
TS: To some extent this association with costlier being of greater quality is an extrapolation from usual market behaviours wherein costlier mass consumer products is associated with better quality. For example, a hotel room, or mobile phone or a car. But this does not apply to medicines which have to meet minimum standards, and where whether it does so is not a matter of perception, but requires laboratory analysis.
KMG: A medicine is a chemical structure. Once you know the structure, it is like you have the recipe and you can make it too. Pharmacopeia standards specify the structure. Generic medicines have a long history and most countries went by this until quite recently. Brand is only a vehicle for promotion. When it comes to biotherapeutics, the originator structure keeps on changing. This too can be addressed, but there are differences. If a healthcare provider believes that a particular company is more reliable, then, he/she should prescribe the medicine by generic name and then in brackets specify the company name, or even brand name. The use of only brand names creates considerable prescriptive confusion and barriers to continuity of care.
YJ: Further to flag another aspect, whereas there is no data that branded drugs are superior to generic drugs, or multinational drugs to Indian companies, the more powerful MNCs have more financial muscle to game the system than even smaller drug manufacturers.
KMG: The MNCs will always position themselves as the followers of gold standard and use the gold standard to manage the competition. So, to give an example, it’s like saying that food in a Dhaba is not safe and only a five star hotel kitchen can provide you with safe food. But we all know that there are small, mid-level restaurants that are known for tasty and safe food too and they need to remain. These small and mid-level outlets have hygienic practices to ensure safety and quality of the food. Regulatory authorities can set standards based on scientific evidence for small and mid-level producers. So, I reiterate my first point, that one must grasp the politics of regulation and its misuse to manage the competition, and instead design it to achieve our public health needs through safe, appropriate, essential medicines. That should be the scientific rationale and evidence in designing our regulatory system. We need not imitate global standards and institutions mechanically thinking that everything in these global standards is scientific and absolutely essential to ensure quality.
YJ: Before I come to the way forward let us consider the area of procurement by the government for public health services. By 1995, the Tamil Nadu Medical Services Corporation (TNMSC) had established a model of how procurement could be transparent, efficient and assure uninterrupted supply of medicines and all consumables of assured quality. In the decades since, only three or four more states have adapted a similar system, notably Rajasthan, Kerala and more recently Meghalaya. Why this poor uptake of a very good model?
TS: Many states have created a TNMSC like institution which has shifted the powers of procurement from the directorates to a semi-autonomous government institution established for this purpose. This is necessary but not sufficient. To ensure transparency, efficiency and quality- there are a minimum set of process requirements that most states do not follow. With respect to quality, it involves mandatorily sending two samples from every batch of medicines supplied to two empanelled laboratories and releasing the medicines to the facilities and making the payments only after the quality is independently verified and certified. And this has to be done within a 10 day period. There are also protocols for empanelling the drug-testing laboratories for quality assurance of the laboratories themselves, for taking action on firms supplying poor quality medicines including black-listing them and even protocols for de-blacklisting, if they comply. We note that protocols for deciding on how much of each medicine to procure based on what is called the pass-book system is an important element of this system and one of the least replicated. If this is not followed orders become more arbitrary and influenced by which drugs have more margins and which suppliers are more favoured. In short, though there are elements of the TNMSC processes that can be improved on, every element is important and must form the baseline for any system of public procurement of medical consumables.
There is another problematic rule in public procurement, where public sector manufactured products are exempt from the rules of procurement. Part of the problem is that such procurement is done from traders associated with the public sector rather than from public sector manufacturing units. If this is the practice, this is only a simple ruse for non-transparent procurement with kick-backs. Even if procured directly from public sector manufacturers with transparent processes, no relaxation of the quality protocols as applicable to other medicines and suppliers need be granted.
KMG: I think there is one more point. I was reading the CAG performance audit reports of public health infrastructures of various states which talk of large time delays between placing the order and supply. There is also, perhaps as a result of this considerable under-spending,. For instance, According to the CAG performance report of Karnataka in 2021-22 the budgeted amount for the medicine procurement was Rs 681.87 crores the released amount was 588.98 crores and the expenditure was only 269.88 crores.
TS: So that is the reason for standardizing time-tested evidence based operational protocols or process elements of the procurement and supply chain management institution. Tamil Nadu rate contracts suppliers every year, with suppliers delivering, required quantities directly to the district warehouses within a month of the order, and samples for quality testing being sent and reports received within a further 10 days. These huge delays in underspending are also due to poor protocols in place. These time standards are important.
That so many state and central government agencies do not follow these robust learnings is a shame. There continue to be sporadic incidents of deaths and dangerous complications due to poor quality medicines in public services. , It is also a matter of the public provider having confidence in their own medicine supply. I have seen that even in prestigious institutes like AIIMS senior specialists do not trust their own hospital procurement to ensure quality medicines, and though this is partly due to the brand name bias, it is much more when procurement systems are not transparent and validated enough to win the providers’ trust.
KMG: This trust deficit is also dependent on how public information is presented and understood. Over the last few years, the CDSCO publishes monthly data on what is called Not of Standard Quality (NSQ) medicines. NSQ is defined under Section 8 of the Drugs and Cosmetics Act, as medications not in compliance with specifications mentioned in the second schedule of the act. Quite often, we do not know what the standards are which of these are violated, and whether these are minor and major, having implications on the patient’s life/health. So, this monthly data on NSQ without a disaggregation is a problematic approach, because instead of providing relief or guiding corrective action, it is actually fuelling confusion and lack of confidence. Ideally, the data should be disaggregated and categorise the major and critical compromises of quality.
YJ: But if there is a sub-standard drug of ‘major’ category detected, is the system geared to track and trace the source and hold them accountable?
KMG: If the supply is directly from the company, which is one rule that a public sector procurement like TNMSC follows, then tracing and holding the manufacturer accountable is relatively easily done. But on the retail private markets, there is one more feature, which is sort of unique in the developing country and Indian settings. That is the large presence of traders who are not manufacturers. They just come to India, procure this medicine in bulk quantity, take it away and market it in their country because there is a huge unmet need. For example, in a place called Bhagirath Palace in Delhi, there is a huge wholesale market for medicines. As per the system, the product goes to a licensed wholesaler, and from then to licensed retailer. Without retail license, the wholesalers are not supposed to sell, right? But in Bhagirath Palace, any trader can go and procure most types of medicines if you have the right kind of contact. There is a grey area where traders can buy from a manufacturer and then and relabel, price higher, and re-sell it and there may be nothing in the laws that prevent it. I am not sure about the scale of such trade and I must look up the correct legal position to find out whether there is a legal vacuum to regulate such practices, but such things are happening. I’m saying that there are different business models out there, and the regulatory system is not capturing all these business models. So, so we have grey areas or a certain regulatory vacuum. The lack of effective regulation to ensure affordable prices attracts various actors to exploit the situation including the fly-by-night operators, which contributes to the circulation of quality compromised medicine
Further, an effective public provisioning of medicines can also play an important role in the elimination of quality-compromised medicines. The absence of effective public provisioning of medicines forces people to go to the market to purchase medicines and being exploited by various actors.
The standards which are set for what is quality, the setting of the protocols. is the Indian Pharmacopoeia Commission for pharmaceutical and the National Institute of Biologicals for Biologics. Are they fit for purpose? Are they playing their role?
The Indian Pharmacopeia needs to play a major role. Pharmacopeias provide the specifications of the medicine. Drug quality testing depends on it. Pharmacopeias needs to be regularly updated. Whenever a new medicine come, they should provide the specifications. Currently for new medicine to get into Indian Pharmacopeia takes years. And as a result, to get their manufacturing or marketing license to introduce a new drug, a generic company has to produce their own dossier. It is like reinventing the wheel multiple times. Why not have a public investment that provides the specifications of at least all essential medicines in the public domain, as a public good, so that anyone with the capabilities can use that and produce the required medicines? That eases compliance with GMP and reduces the costs and time of introduction generic versions.
When we send our drugs for testing to see whether it has sufficient quality, are there enough drug testing laboratories? Is there a bottleneck there?
KMG: I think we do not have a major problem with the number of laboratories available for the testing. According to the ministry of Health website we have 8 central drugs testing laboratories and 23 government drug testing laboratories set up by the state governments. There are also a number of quality certified private laboratories that are available for empanelment. Though, we do not have a clear picture of the efficiency of these labs and resources available, these labs do provide an effective and timely quality evaluation. We do need to invest further in this area, definitely in developing rapid screening technologies like portable screening technologies etc. This can reduces the burden of labs.
YJ: I’ll have one quick question, which is a little off the track. I’ve been told by some chemists that there is nothing like expiry of chemicals and these two or three year expiry dates are more marketing strategy to keep on producing more drugs. I’m not talking about biologicals, which like food, will degrade. But do chemicals like paracetamol or ibuprofen need these expiry dates?
KMG: Yogesh, I am not a chemist nor have a chemistry background. So, I cannot answer that in a scientific way. But as a lay person, I do have the same question. You have a molecular structure, and that structure cannot spontaneously change Quality should not go down unless exposed to heat or water or contamination, So I would think, reasonable packaged and preserved under the right environment, most drugs should retain their potency.
YJ: Because now the rule says that you have to return your expired drugs to the company that is producing it. I hope that they’re not just repackaging and selling it again?
KMG: I hope not too. I do not know. Even elimination has its protocols. Antibiotics for example have to be disposed of by integrating into cement or some such requirement.. Interestingly, as per Indian standards, there is no expiry date for any alcoholic drink containing more than 10%. That is why you will also see for some of the products, there is no expiry, it’s only a “ best before” date.
YJ: We discussed public procurement for public services. Any comments on public procurement for “Jan Aushadhi pharmacies”- the retail pharmacies that government runs to make generics available? Is there a TNSMSC equivalent quality assurance in place?
KMG: Jan Aushadhi has its own list of empanelled and certified suppliers who are necessarily manufacturers. But there are frequent short supplies and stock outs. This is also a feature of central procurement for medicines against TB, HIV etc. These are managerial issues, and hopefully will be overcome.
But I would like to flag another issue. Last year, Indian Pharmaceutical Alliance (IPA), an association of top Indian top companies wrote a letter asking that Jan Aushadhis should not substitute prescribed medicines with generic equivalents, as that would be a quality issue. But that would defeat the purpose of these pharmacies. Concerns expressed in the letter have no basis because Jan Aushadhi is procuring from quality certified manufacturers and testing each batch of medicines received. I think we must insist that all prescriptions always have the generic names, even if the name of the preferred manufacturer is also specified by the prescriber. The use of only brand names puts patients’ lives at danger because of possible misinterpretations and prevent continuity of care across providers.
YJ: What are the challenges with respect to quality assurance of biologics- a quick overview would be welcome.
Pharmaceuticals are made from chemicals whereas biologics are made from living cells. Biologics includes vaccines. Biosimilars, is to biologics what generics is to pharmaceuticals. Vaccines do not have a pathway for approval of generics/biosimilars- only the originator vaccine prevails. Biosimilar/Generic approvals is only for biologics used for therapeutics i.e .bio-therapeutics. The pathway to such approvals in India are called GUIDELINES ON SIMILAR BIOLOGICS: Regulatory Requirements for Marketing Authorization in India, 2016
Countries like India and Asia in general, had biosimilars and biosimilar guidelines in the 90s onwards. Biosimilars and biosimilar regulation came into European market only in 2005. But when the EU regulation came, then WHO adopted a regulation based on EU regulation. And we adopted these and we remain hesitant to change these. We changed our existing regulation to comply with that, and as a result, we have included requirements like comparative clinical trials and animal trials. In 2021-222, WHO and the UK changed the regulations to say that there is no need of a mandatory comparative clinical trial . But our regulators are not ready to change it, because we are waiting for the US and EU to change. Similarly, the UK, the USA and the EU are no longer calling for animal studies but we have not changed the rules yet. This is because of technological advances which lead to better characterization and replication of the molecules. Had we changed our biosimilar guidelines in line with these changes, the cost of development could go down by 60 to 70% and biosimilars would have come much more easily in the market at a reduced time period also. Also, now, it takes five to seven years to develop a biosimilar, but we have to amend our guideline. Quality assurance is not the bottleneck here, but access and affordability is, and we need to learn to consider all three together.
YJ: I wanted to ask about the regulatory regime. There is new requirement of Biological Availability/Bioequivalence (BA/BE) Studies for approval of generics that is being called for. Some are even calling for such studies on all medicines.
KMG: There are some situations where it is necessary (medicines which are having solubility issues) , but many in which it is not. Compulsory BA /BE studies in all generic approval is unwarranted and without any scientific basis.
Difficult to get into all the details but the principle is that the rule has to be appropriate to fit for the purpose, and not a blanket rule. The drug regulator has to balance considerations of quality and efficacy of the medicine with affordable access. And it is just not true considerations of affordable access always compromise quality and safety. There are science and technological tools available to ensure quality and safety and at the same time to facilitate affordability.
YJ/TS/KMG: We try and summarize some of our main observations with respect to the way forward.
Our first observation is that one of the most reliable and feasible ways forward is to increase the proportion of medicine accessed through public health facilities and Jan Aushadhi clinics and the pre-condition of this is scaling up and universalising the time tested evidenced based protocols for procurement and quality assurance pioneered by TNMSC and later Rajasthan. Even these require improvements- but this is the minimum standard.
With respect to medicines accessed through the private markets, the approval for a new drug for the first four years is in place. However, there is an urgent need for state drug authorities to ensure periodic inspection and renewal of both manufacturing and marketing approvals, after this initial period. Protocols for doing so, standardized by CDSCO need to be available in public domain and compliance monitored. The number of staff required under a state drug authority would be computed from the requirements for ensuring regular inspections and testing for verification of quality, both in manufacturing units, and in intermediate warehouses and in retail. States would probably require financing support to close staffing gaps. Enforcement may also require legislation.
There is also an urgent need to strengthen the regulation of the quality of APIs, both those imported and manufactured locally and close quality related regulatory gaps with regard to different forms of contract manufacturing and different business models of trade and distribution. While sharing of medicine quality gaps as detected throughsurveys is welcome this should go along with details of the type of gaps and a track-and-trace exercise of tracking to gaps to their source and recommendations on correctives.
Much greater proactive efforts are required to ensure quality of export of drugs to other LMICs especially those with weak regulatory systems. Adherence to the WHO certification scheme on the quality of pharmaceutical products moving in international commerce is a good starting point. Importers should be able to access data regarding the quality certification status of Indian manufacture and drugs under export. As an act of solidarity and soft power, proactive measures to build testing capacity and regulatory systems in other LMICs would also be appreciated.
Together these measures would not only ensure the safety and efficacy of medicines, but by building confidence in the regulatory systems and therefore in generics approved by it, it would also contribute to affordability of medicines and lower the costs of healthcare.
Much of this should have been done a decade ago. But it is not too late to start now.
Acknowledgments:
We gratefully acknowledge Ms Roubitha David for her contribution to recording, transcribing and editing the conversation, Ms. Riya Raghunath for the illustration and Mr. M. Hasan for the IT support.
About the participants:
K. M Gopakumar is a Senior Researcher and Legal Advisor at Third World Network (TWN) and based in New Delhi, India. TWN is an independent, not-for-profit organization that carries out policy research and advocacy on issues around trade and development, with a focus on third world countries. His work in TWN focuses on the global IP regime and its implications on on development. He has published extensively on issues related to access to medicines and is a well known, often cited expert on the many challenges related to access to medicines in developing nations.
A good conversation, bringing one upto date with current issues, regulations and regulatory bodies and systems.
However, I feel you did not touch on the elephant in the room – the doctor who is the contract mediator between the industry and the client (patient). Doctors really need to be aware of these issues and the economics involved – to the individual patient and the system as a whole. In the case of the TNMSC and the Janaushadhi, the doctor is the one who can game the system. When the TNMSC was set up the government doctors opposed it. JIPMeR conducted a training programme for government doctors on the concept of essential drugs and need for a system like TNMSC. Unfortunately the initial efforts of TNMSC have got diluted by my reckoning.
Similarly doctors phoo phoo the Jan Aushadhi and generics and patients end up paying through their nose. I have many diabetic friends who are saving a lot of money through the Jan Aushadhi. But they hide the fact from their physician
Good conversation. It misses the question of behavior of India’s large pharma companies which is now structural. My ICSSR report brought it out in detail. My EPW article in 2020 covered this issue with data based evidence building undertaken at the time I was in ISID. Now I don’t have access to databases. But my understanding is that the source of the problem remains the same- low road to capitalism.
Thanks. The whole quality red herring is a byproduct of companies being allowed to stick a brand name on a generic drug. Abolishing Brand Names while allowing a corporate name as a tag, e.g. Telmisartan – Cipla would establish more effectively the fact that generics are equivalent and still ensure that the corporate has enough skin in the game to assure quality. Marketing budgets at pharma companies can be eliminated allowing them to spend the money on quality and innovation.
Another great one: something we’re not taught adequately either in medical school or within public health
Super Sir, my suggestion is that we should move to QR code in every strip of medicine so that Public can understand where it is manufactured under which license, and it should be linked with the report of the lab, which tested the quality, including bio availability
Dear Yogesh,
To look at the issue of expiry dates, let’s see what pharma companies do with their ‘expired’ stock. Typically, most companies collect back (at least try to) expired drugs. They do not destroy them; procure a new QC pass report and repack them with a new expiry date. Except for injectables, where the risk of contaminants like fungus etc. is far too high.
For common drugs, if stored properly, nothing much can happen unless exposed to higher temperatures (more than 40°C) for long or kept in condensing humidity. Under normal conditions, some degradation of the active compound will occur, but how much? Secondly, a serious thought on the toxicity of degradation products would be essential.
Typically, 1-5% (only a guess) degradation of the active compound would be expected within the duration of ‘shelf life’ of a drug and mostly degradation products are only as ‘toxic’ as the primary active compound. It is essential to be mindful that the variations in the bio-availability of active compound among any set of patients, are much more than the possible variations which might occur after the ‘expiry’ date of a drug.
The pharma companies and the regulators do not wish to leave anything for a person (patient or doctor) to decide for themselves and we are happy with it.
Thank you for writing,
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An online discussion with Dr Vinod Paul which is immediately relevant to our conversation.
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