This is not the best moment for the biopharmaceutical industry in India. In the last two years, there have been reports of product recalls, failed manufacturing-facility inspections, revoked approvals and over $500 million in fines for Ranbaxy Labs, one of the top pharma manufacturers in India, for falsified generic drug data.
However, as BioPharma Dive has pointed out before, strenuous reform efforts are underway. And quite frankly, the world depends on the productivity of Indian pharmaceutical manufacturers to meet the need for affordable generic drugs. In fact, in the U.S. alone, 40% of all OTCs and generics are imported from India, including fixed-dose combination (FDC) drugs.
In 2001, Indian authorities enacted a regulatory rule requiring that drug manufacturers prove that a drug is both safe and effective, including FDCs. But that rule was subsequently downgraded in 2005.
Indian laws governing the creation and approval of FDCs are inconsistent with World Health Organization (WHO) guidelines. While the WHO guidelines focus on scientific efficacy and safety data, as well as the ability to make a solid case for medical necessity, “convenience” is an acceptable basis for approval of FDCs in many Indian states.
When marketing an FDC drug, there are many angles that may seem compelling at face value, but offer little in the way of therapeutic benefit. There's a tendency for the "more is better" logic to dominate the discussion, without regard for drug/drug interactions or non-therapeutic redundancies.
For example, pediatric formulations of nimesulide and paracetamol, both NSAIDs, can not only induce hypothermia, but lead to shock. With respect to adult formulations, the combination of the NSAID diclofenac and serratiopeptidase, which is often used as an anti-inflammatory, can lead to serious gastrointestinal (GI) bleeding.
In addition, FDCs of quinolones and nitromidazoles are heavily prescribed to treat all types of infections, ranging from dental infections, to GI infections, to pelvic inflammatory disease, despite the fact that this combination has not been validated. This type of FDC is often prescribed when there is not a precise diagnosis, but it is clear that some type of infection is occurring. The result is an exponential increase in antibiotic resistant organisms and infections that can become untreatable.
Because the "more is better" approach often drives clinical reasoning when it comes to pain management, there has been a tendency to develop combined-analgesic FDCs, despite the fact that there is little evidence of increased effectiveness. In reality, there is no synergy between two drugs that target the same enzyme in the same way—but selling two drugs at once is a more profitable proposition than selling just one.
Global reliance on India’s HIV FDCs
When it comes to certain therapeutics areas, especially HIV and AIDS, FDCs are a godsend for many patients. According to Mark Menning, Managing Director and Co-founder of Actera Pharmaceuticals (a formulation innovation company that specializes in FDCs), “When resistance-development risk factors are a concern, such as with HIV, FDC products facilitate improved compliance, reducing the risk of poor-adherence related resistance development."
"For example if a patient is taking triple therapy for HIV using single agent drugs, and runs out of one or two of the medications, but doesn't refill their full triple therapy prescription immediately, this is a problem. In such case, a patient may be taking mono or dual therapy for a period of time, becoming prone to resistance development—either to a specific drug or worse still, its entire class. When using FDC products, especially three-in-one single-table regimens, this partial compliance scenario is less likely to contribute to drug resistance development.”
As BioPharma Dive noted in an earlier feature, 85% of all drugs in certain developing countries, including most of sub-Saharan Africa, come from India. There is a program, PEPFAR, which exists specifically for the purpose of providing donor-funded HIV relief to developing countries where patients cannot afford antiviral medications. India is the primary source of these antiviral drugs, which are offered at affordable prices. In fact, the FDCs that India manufactures for PEPFAR distribution are stringently regulated and much needed.
There have been attempts to reform the Indian FDC market, including massive recalls that were basically ignored. One problem is that, if the regulatory authorities in one state approve an FDC, the pharma industry is able to market it throughout the country.
That means that in states with more conservative, regulatory-minded drug-approval processes, such as Maharastra and Gujarat, drugs that would otherwise not be available are freely distributed.
Guidance from the Committee for Medicinal Products for Human Use (CHMP) in Europe heavily informs that WHO approach to FDCs and represents comprehensive guidance, which, if implemented, could result in positive reforms. Several of the most important FDC-related guidelines state:
- At least one of the APIs should be on the Essential Medicines List (EML) of the WHO or India’s National List of Essential Medicines (NLEM).
- Dosing should be precise and studied in population-based trials.
- The combination should be determined safe and effective, and ideally provide advantages of the individual drugs in the FDC.
- The FDC should have a lower cost than buying each of the individual drugs separately.
- The FDC should facilitate the reduction of doses of the individual drugs, or reduce side effects.
- Pharmacokinetics should be similar and should not be affected by combining the individual drugs.
- There should be no unfavorable interactions between the component drugs.
- Each of the individual drugs should have different mechanisms of action.
In the final analysis, reform is possible, but challenging. The development of FDC drugs as a category is here to stay, but restraint and rigorous regulatory oversight is needed if these drugs are going to benefit patients in India—and the rest of the world.