Among all the issues I have written over the last month since the Supreme Court refused to admit my petitions, there is no better than the issue than this one when it comes to how the current regulatory structure intentionally creates and encourages a market for substandard drugs in India. The incompetence of the regulator coupled with the collusion and influence of the powerful pharmaceutical lobby over policy making is so obvious in this case that it makes for a text-book case of how not write and enforce regulation for public health.
Over the last several years, there have been increasing concerns about the quality of medicines manufactured and exported from India to the rest of the world. Violations of compliance with Good Manufacturing Practices (cGMP) and Good Clinical Practices (cGCP) have been highlighted by regulators from the North America and Europe for product that is manufactured in India and exported to these continents. An equally important issue which has received almost no public attention is the fact that Indian law currently does not compulsorily mandate demonstration of therapeutic equivalence and stability for generic drugs sold in India. Although the absence of these regulations in Indian law does not affect regulated markets like the US and EU which impose strict quality standards for their drug supply, they do have a direct bearing on the health outcomes of patients in India and other third world countries which import drugs from India.
Before explaining the system of drug approvals in India, it is first necessary to understand the importance of bioequivalence and stability testing.
The Thalidomide tragedy in Europe in the 1960s was one of the defining moments of the modern pharmaceutical industry. The tragedy, led to the introduction of a legal framework which mandated rigorous clinical trials, wherein a new drug’s safety and efficacy had to be established in human patients before being approved for therapeutic use. Clinical trials mandated post the Thalidomide tragedy are expensive and risky affairs; expensive because they require sound statistical models for the number of patients and expected outcomes and risky because chemicals (and now biologicals) don’t necessarily behave the same way in human body as they do in the laboratory. Legislation like the Hatch-Waxman Act of 1984 created a new regulatory pathway which allowed generics (identical copies to the innovator product) to enter the market if the regulator was satisfied that the generic drug was bioequivalent to the innovator product. Unlike clinical trials which are conducted on a patient population, a bioequivalence (BE) study is carried out on healthy subjects and is therefore significantly cheaper and safer when compared to full scale clinical study. The science behind a bioequivalence study is relatively simple. All drugs have what is called the API, the active ingredient which cures the ailment along with other filler material called excipients. The way the API and excipients come together to form the dosage (e.g., a tablet, or capsule or a syrup or an injection) requires a special process, which is based on established science. Parameters like particle size, blend uniformity, tablet weight, breaking strength, density, flow property, punch penetration etc. all have a material impact on how fast the dosage dissolves (established by a dissolution test), absorbed into human body and becomes therapeutic. Conducting a BE study evaluates how a particular formulation behaves in the bloodstream of a human being when compared to the innovator drug it copies demonstrating whether the intended therapeutic effects can be reasonably guaranteed in human physiology.
If a generic drug fails a BE study, it means that it doesn’t behave in a manner similar to the innovator drug. This is not necessarily bad in itself. The innovator drug has very specific characteristics, called the Pharmacokinetic (PK) and Pharmacodynamic (PD) profile that shows how it behaves in the human body. If the generic formulation fails the BE study, it means that its method of action is different from that of the innovator drug it intends to copy. The science behind the innovator drug and its therapeutic effect is established by the innovator company through clinical trials. Therefore, if the generic drug behaves differently, it means that the regulator then has to evaluate whether the generic formulation has the same therapeutic effect, side effects and overall characteristics as the innovator drug does. This requires a clinical study. The route of approval for such a product is different and is not govered by the regulations that accord approval for generic drugs. If however, a BE study is not conducted, there is absolutely no way to verify the manufacturer’s claim that its drug works at all, let alone work as well as the innovator’s drug.
The generic pharmaceutical industry in India, in conjunction with Indian clinical research organisations (CROs) have a long history of manipulating bioequivalence studies required by the American and European regulators. The Ranbaxy scandal, which first came to light in 2003, exposed the scale of fabrication and manipulation of bioequivalence studies being conducted in India at Vimta Laboratories. Recent investigations by the French regulator ANSM at GVK Bio, the US FDA at Semler Research and the German Regulator BfArM at Alkem Laboratories have exposed how Indian CROs continue to manipulate bioequivalence studies for their clients – mostly the Indian pharmaceutical industry.
The problem in India today is that generic drug companies which enter the market after the expiry of the ‘new drug’ status (4 years after first approval is granted in India), are not required to conduct bioequivalence tests. Manufacturing licenses are given to these companies by State Regulators (SLAs) who are not required by the law to confirm that the product they approve in fact works as intended and offers any therapeutic benefit to patients. Lets reflect that for a second; what this means is that the so called medicine that is approved by the state regulators is no better than snake-oil.
This nonsense is based on a faulty reasoning that anyone can manufacture drugs, without a modicum of scientific knowledge, experience or process controls. How then does the regulator satisfy itself that the generic formulation is as good as the innovator drug? The answer is simply that our SLAs have absolutely no information on whether Indian generics drugs are even half as good as the innovator drug. In July 2013, an expert committee headed by Dr. Ranjit Roy Chaudhury which was constituted by the Government of India to formulate a new policy on drug approvals and clinical trials had recommended that BE studies be made compulsory for all generic drugs sold in India. This recommendation was placed before the 47th Drugs Consultative Committee (DCC), a statutory committee consisting of representatives of all state drug controllers, the central government and the DCGI.
In this meeting, the DCC discussed the Expert Committee’s recommendation and rejected it on the grounds that India lacked the infrastructure to carry out such studies. The exact reasoning of the DCC is reproduced below:
“The recommendations of the Prof Ranjit Roy Chaudhury Committee in respect of Bioavailability or Bioequivalence (BA / BE) studies conducted in India were deliberated in detail. The members were of the view that BA / BE studies in respect of drugs manufactured in the country shall be insisted whenever there are issues relating to patient safety and variable bioavailability. As the infrastructure for conduct of such studies is not uniformly available in the country it cannot be implemented as a rule.”
In the same breath however, the Committee recommended that BE studies be conducted for the purposes of export consignments if foreign countries so require such approvals. The hypocrisy of the DCC is absolutely stunning. It is well documented that there are a plethora of Clinical Research Organizations (CROs) in the country that conduct these BE studies for the same Indian manufacturers who intend to sell their product in the western markets. Their argument that the infrasture to conduct these studies is not uniformly available is ridiculous. Going by their reasoning, each state in the union ought to have its own manufacturing facility that serves that particular region. That is clearly not so; we know where most of our medicine manufacturing facilities are. They are in Himachal Pradesh, Andhra Pradesh, Uttarakhand, Maharastra and now in Sikkim. Why is it that we accept medicine made in a different state but will not accept a BE study conducted wherever the facilities are? So this line of reasoning is purely specious.
Why then are Indian citizens being subjected to medicines of questionable therapeutic value when compared to the drugs that are being exported to foreign countries, often manufactured by the same companies? Clearly, infrastructure exists to conduct BE studies for drugs made for export; the DCC recognizes that. This double standard, especially by a statutory body which is responsible for formulating regulations govering quality of medicine in India is criminal.
This is the reason why so many of our doctors switch medication so often. It is also the reason why they prescribe steriods along with the actual medicine because their faith in the medicine to work as intended is so low. Any honest Indian physician will tell you privately that not all generic drugs work as advertised; the only option for them is to switch brands and cross their fingers. This is the reality of healthcare in India and the consequence of a corrupt and incompetent regulator who is hand-and-glove with the industry whose powerful lobby dictates the terms of the healthcare policy for the country. And the Supreme Court thought that this was an academic issue.
The list of double standards between the drugs which are exported and those which are consumed by patients in India also extends to the issue of stability testing. The US & EU require rigorous stability studies to be conducted on any drug being sold in their markets. ‘Stability studies’ are required to ensure that drugs do not breakdown due to atmospheric conditions such as temperature and humidity during their storage and that the drug is stable till the claimed date of expiry on the label. These studies are conducted by placing a sample of the drug in a controlled environment such as a refrigerator and subjecting it to differing atmospheric conditions to test whether the drug decomposes. Parameters for stability testing differ amongst different countries depending on their climate. Globally, most regulators recognise four zones, depending on their climate. These are Zone I (Temperate), Zone II (subtropical, with possible humidity), Zone III (hot/dry) and Zone IV (hot/humid). India falls in Zone IV.
Stability testing is of paramount importance in a country like India because of our hot and sometimes humid climate which creates conditions conducive to their degradation. A drug which fails stability testing will not have the same effect on patient as a stable drug. In the worst case, the products of the drug’s degradation can lead to serious adverse effects. In either case, public health will be significantly compromised. The DCC, in a meeting in its 46th meeting held in November, 2013 had concluded that the lack of mandatory stability testing for generics licensed by SLAs was a ‘serious lacuna’ in the law. The Committee had unanimously recommended that the Drugs & Cosmetics Rules, 1945 be amended to make stability testing mandatory for all generic drugs, not just those which are in the ‘new drug’ category. However the rules have not amended since; almost two and half years post the committee’s recommendation. One can only surmise why.
There are very few barriers to setting up a manufacturing facility to produce drugs for the Indian market today. You need to know no science, no understanding of human physiology, no appreciation for bioavailability and bioequivalnce and no commitment to patient safety. The decisions of the DCC clearly attest to this fact. Regulatory capture by the powerful industry lobby that intentionally frames regulations with loopholes is the reason why our drug supply has so many substandard drugs; and as a country, we have no systems and processes in place to understand the long term impact of this malfeasance on our citizens.
As the pharmacy of the developing world, lax Indian regulations affect not only Indian citizens but also the weak and diseased in the several countries across Asia, Latin America and Africa. In refusing to admit my PILs, the Supreme Court now has given the industry and the regulators a free hand to continue with business as usual.