In April, the Central Drugs Standards Control Organisation rejected pharmaceutical company Cipla’s application to register a HIV drug pellet formulation used for treating children with HIV. The drug regulator’s contention is that clinical trials for the drug combination of lopinavir and ritonavir in pellet form have not been conducted in India.

Registering the drug would have allowed the National AIDS Control Organisation to buy and use the drug to address the problem of frequent stock outs of paediatric HIV medication in the country.

This is the second time that the drug regulator has rejected such an application. The regulator is meeting again on May 25 to again consider Cipla’s plea to register lopinavir-ritonavir pellets.

The lopinavir-ritonavir drug combination is the backbone treatment regimen for HIV positive children below three years of age. Cipla had conducted clinical trials in Uganda and Kenya and had already been supplying the drug pellets outside India. The company sought a waiver for clinical trials among the Indian paediatric population.

“We are very much willing to register the pellets of lopinavir-ritonavir in India,” said Denis Broun, director of public and government affairs for Cipla Global. “However, we do not believe that it is necessary to do further clinical studies for a product that is used in several countries. We have tried to get it registered in India several times and we really hope that the Drugs Controller General of India will accept to make it available to Indian children living with HIV.”

The Drugs Controller General of India is the official at the Central Drugs Standards Control Organisation who approves licences for all the drugs to be sold in the country.

Pellets versus Syrup

The lopinavir-ritonavir pellets are known to be better forms of medication than the syrup of the same drug that has been in use. The syrup contains 42% alcohol – equivalent to the alcohol content in whiskey. It also needs to be refrigerated and is often rejected by children because of the bitter taste. Cipla’s product in the pellet formulation has no taste and no alcohol and can be stored at room temperature. The lopinavir-ritonavir pellets are packaged as micro-tablets inside a capsule that can be opened and mixed with a child’s food.

The HIV control programme under NACO has, so far, used the syrup to treat HIV positive children. In January, there was an complete stock out of the syrup all across India affecting more than 500 toddlers below the age of three. Cipla had stopped manufacturing the syrup in 2015 and NACO’s supplies from the company lasted only till the end of 2016.

In February, NACO made an emergency purchase of the syrup from McNeil & Argus Pharmaceuticals in Ambala, Haryana, a company that had only manufactured this product twice earlier. NACO only bought three months’ worth of syrup. McNeil & Argus Pharmaceuticals’ syrup does not meet quality assurance standards set by the World Health Organisation and has not passed the required testing, activists said. The Drugs for Neglected Diseases initiative recently donated 1,000 bottles of the lopinavir/ritonavir syrup from Abbvie, which is not registered in the country but got a waiver from the drug control authority.

(Photo credit: McNeil & Argus Pharmaceuticals.)

HIV activists are keen that Cipla registers the lopinavir-ritonavir pellet formulation as a long-term solution to the problem of procuring paediatric HIV drugs.

The World Health Organisation in 2015 recommended that the drug in pellet form should be included in national HIV treatment guidelines of all countries.

“Failure to authorise the lifesaving medicine in India by the CDSCO is a huge setback for the National AIDS Control Organisation which is trying to procure the pellet to address the current situation,” said Leena Menghaney from the Access Campaign, Médecins Sans Frontières.

The Global Fund for AIDS, Tuberculosis and Malaria recently allowed their rapid supply facility to finance the supply of these drugs in India for six months. The facility responds to emergency orders of essential drugs during stock outs.

“Clearing these drugs for the paediatric population is definitely required,” said Dr Soumya Swaminathan, director general of Indian Council of Medical Research. She said that experts from NACO and other people working on HIV control will be present in the review meeting on May 25.

No HIV expert consulted

The Central Drugs Standards Control Organisation first rejected Cipla’s application to register the lopinavir-ritonavir pellet medicine in December. The Drugs Controller General of India GN Singh issued a circular on March 20 for fast track regulatory approval of HIV drugs, which said that clinical trials can be waived for HIV, hepatitis B and hepatitis C drugs recommended by World Health Organisation and needed in extreme urgency.

During the last stock out of the lopinavir-ritonavir syrup, civil society members urged Cipla to try to register the drug again based on Drug Controller General of India’s new guidelines. The Central Drugs Standards Control Organisation committee insisted on a local clinical trial despite this circular and rejected the application once again. Cipla has completed the first three phases of clinical trials in Uganda and Kenya. If the drug regulator had allowed the drug to be registered, the company would have to conduct the fourth phase trial at government hospitals in India with paediatric HIV patients. Fourth phase trials are designed to study long-term and latent effects of drugs.

Activists said that there are enough provisions in the Drugs and Cosmetics Act to grant a waiver for clinical trials, especially in case of public interest and emergencies.

“There are provisions in the Drugs and Cosmetics Act to grant a waiver of clinical trial in public interest on the basis of data available in another country,” said S Srinivasan, who runs a generic drug manufacturing company in Vadodara called LOCOST. “This case is an unfortunate lack of coordination between two arms of the government – NACO and CDSCO – from the same ministry. This is a tragic instance of government short sightedness.”

In its April meeting, the subject expert committee of the Central Drug Standards Control Organisation that considered Cipla’s application did not have an HIV expert, a paediatrician or anyone from NACO present.

“There is a fundamental weakness in the manner in which subject expert committees are functioning, particularly in the area of neglected diseases such as paediatric HIV, “ said Menghaney. “It is important to call an expert in the subject such as an paediatrician from the public sector who is treating infants and children living with HIV to also participate in the discussions.”

Broun called that the rejection of their application a missed opportunity.

The Drugs Control General of India GN Singh did not respond to calls or messages from

In March, when spoke to NACO deputy director general of NACO Dr RS Gupta, he was keen to get Cipla’s product registered with the drug regulatory body. But on Monday, he said, “The pellets are just an alternative. Currently, we have the syrup. The pellets are not required.”

However, he is also watching the outcome of the drug regulator’s May 25 meeting.

Meanwhile, there is the constant threat of another HIV drug stock out. “We need a long term solution to this problem and the NACO has to be serious about addressing this issue,” said Manoj Pardesi, general secretary of National Coalition of People Living with HIV in India.