ICYMI: India's fixed-dose combo problem: Too much of a good thing?
The Indian pharmaceutical industry is highly productive and populated by well-educated, driven researchers and pharmaceutical executives. As the third largest pharmaceutical market in the world, with $21 billion in annual turnover and 345,000 employees, this market continues to grow rapidly. The ability of scientists to reverse-engineer existing drugs has created a robust generics industry that provides much of the world, including the U.S., with a large majority of their generic and OTC products. In tAmerica alone, 40% of generics and OTCs come from India.
Yet, the Indian pharma industry is challenged on all sides by quality-control issues, product recalls, drug importation bans, and even withdrawn approvals that cost hundreds of millions of dollars in unearned revenues—as recently happened to Ranbaxy Labs.
FDC drug development run amok?
One area of concern is the aggressive development, approval, and marketing of fixed-dose combination (FDC) drugs that combine two, three, or even four drugs. According to a special report to the Lancet in January, “FDCs are a remarkable feature of the Indian pharmaceutical market, with rising approvals reported between 1999 and 2011.”
There are more than 1,100 FDCs available for domestic consumption in India, including for prescription FDCs, over-the-counter drugs, multivitamins, hand creams, and nutritional supplements. Some are ineffective. Some are dangerous. And some are both. Between 1971 and 2012, there were 2,972 new drug approvals granted by the Central Drugs Standard Control Organization (CDSCO), and 1,098 of those were FDCs. In fact, 63% of FDC approvals were granted between 2005 and 2011.
While there are many advantages to FDCs when they are rational, effective, and safe, the Standing Committee on Health and Family Welfare in India has criticized the regulatory authorities for looking the other way as large numbers of FDCs are approved by state regulators without any oversight or approval from CDSCO. There have also been reports that many of the FDCs are approved without proper clinical trials.
There’s a downside, but there’s also an upside
There are several theories about what has driven the spike in FDC approvals. One problem is that the most current version of the Drugs and Cosmetics Act, which dates back to 1940, has been updated on an ad hoc basis numerous times. There is a lack of clarity around many critical areas where regulatory oversight is necessary. For example, there is still confusion between what it means for a drug to be "effective" versus "efficacious." Drugs are effective if they work in real-world situations, while efficacy refers to drugs working in ideal, carefully controlled circumstances.
Another problem is the fact that the rules governing clinical trials in India are not sufficiently rigorous. For example, while regulators require that clinical trials must be conducted starting from phase I if a drug is discovered in India, drugs discovered in other countries can automatically move into phase III trials. In addition, there are no requirements about the minimum number of subjects or research sites needed to conduct a trial.
Sean Dalziel, Managing Director and Co-founder of Actera Pharmaceuticals (a formulation innovation company that specializes in FDCs) says there is another side to FDC development in India. In fact, because of its unique generic-manufacturing prowess, India is making an important contribution to global health, while adhering to the strictest regulatory guidelines. “In support of the PEPFAR (Presidential Emergency Plan for AIDS Relief), the FDA reviews product applications of FDCs, with many, if not most, of the product sponsors in India," said Dalziel in an interview with BioPharma Dive. "There is a great deal of regulatory oversight involved.”
PEPFAR and Patents
Under the PEPFAR program, the FDA’s regulatory review process and the quality standards for manufacturers are as rigorous as they are in the U.S. Because of certain patent laws, the FDA generally grants "tentative approval" to the FDCs that are bound for developing markets. They are then distributed to regions where patients rely on their availability.
Indian pharma's ability to address the needs of three million-plus HIV-infected people in developing regions of the world dates back to the 1970 Indian Patents Act, which abolished pharmaceutical patent protection, to ensure widespread public access to drugs by taking economic circumstances into consideration.
Because of that law, Indian pharmaceutical manufacturers were able to develop triple-combination anti-retroviral drugs (ARVS) at a fraction of the branded costs. Even when India reintroduced patent protection in 2005, a special interpretation of the intellectual property agreement governing global trade allowed India to continue manufacturing generic ARVs.
The world depends on Indian drug manufacturers
India’s expertise and productivity in manufacturing generic drugs is challenging because of its large scale, but it also serves an important purpose. About 40% of generics and OTCs in the U.S. come from India, 85% of all drugs in Sub-Saharan Africa are from India (including HIV, cancer, and heart disease drugs).
As Indian pharma manufacturers confront a series of recalls and failed facility inspections, income has dipped and serious reform is underway. But at the same time, development and manufacturing must continue in the interest of the greater good.