Wrong at Every Step: The Licensing of HPV Vaccines

by Nalini Bhanot and Kalpana Mehta

Medicines are a commodity consumed by all of us, and they are the only commodity about which consumers cannot make any informed choices except to buy and consume whatever is prescribed or dispensed to them. It is the responsibility of the Central Drugs Standard Control Organisation (CDSCO) to ensure that these are efficacious and safe before licensing them, monitor their use once marketed, and ban those that are found to be hazardous.

In May 2012, the Department-related Parlia-mentary Standing Committee on Health and Family Welfare brought out a scathing report on the functioning of this critical regulatory authority, and their report, in many respects, mirrors the experience of health activists with respect to the regulation or rather mis-regulation of drugs and vaccines. The Standing Committee’s analysis was detailed and exhaustive, and we hope that this report will spur the government to take commensurate action in removing gross anomalies.

The most shocking revelation of the Committee’s report was that the CDSCO’s stated mission is to “meet the aspirations…. demands and requirements of the pharmaceutical industry†. Even market-oriented economies like the US and Australia run their respective Departments in the interest of public health. The USFDA’s mission is “protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs†, while that of the Australian TGA states: “Safeguarding public health and safety in Australia by regulating medicines….†Little wonder then, that activists have found many decisions of the CDSCO to be pro-Pharma companies and against the interests of the people.
In addition, the Committee expressed grave concern regarding the competence and profes-sional qualifications of the Drugs Controller General of India (DCGI), who heads the CDSCO, in comparison to its counterpart in other countries. The Department was also substan-tially understaffed, which inevitably prevented it from discharging its assigned functions efficiently.

For example, a recent petition filed by the All India Drug Action Network vs Union of India points out that in our country 100,000 medicines are being marketed regardless of whether they are useful or safe, whereas in the US and Europe, only 2000 types of drugs are licensed for sale. Once licensed, banning or withdrawal of drugs—that have proven to be harmful or ineffective—has been nearly impossible as the Pharma companies fight tooth and nail to maintain the status quo.
In a systematic analysis of the CDSCO’s func-tioning, from pre-approval to post-licensing pro-cesses, the Standing Committee found a large number of violations with respect to the drugs randomly chosen by it for study. These viola-tions are juxtaposed against the violations discovered by the authors in the case of two vaccines—controversial enough based on their safety and efficacy profile, to rouse more than seventy groups across the country in opposition to their introduction in India.

Vaccines under Consideration

Two vaccines, supposed to prevent cervical cancer, were licensed by the DCGI in 2008. Gardasil (marketed by Merck) and Cervarix (marketed by GlaxoSmithKline) work against two out of the 15 strains of Human Papillomavirus (HPV strains 16 and 18), believed to be most commonly associated with cervical cancer. Gardasil also protects against strains 6 and 11, which cause genital warts. Till date there is no scientific evidence to prove that these vaccines prevent cervical cancer. This is a slow growing cancer, which can take 20-30 years to develop, and research with these vaccines is not even 10 years old. Besides, HPV strains 16 and 18 cover 70 per cent of HPV infection only; hence all girls and women (vaccinated or not) will still need periodic screening, such as pap tests, to guard against cervical cancer. They are believed to be most effective when administered to girls in the age-group of 9-15 years, before they become sexually active as HPV is a largely sexually transmitted viral infection.

Importance of holding Clinical Trials
before Licensing

One of the most sensitive responsibilities of the CDSCO is to approve new drugs for marketing (both manufacture and import) in the country as empowered by and in compliance with Rule 122 and Schedule Y of the Drugs and Cosmetics Rules 1945.
The objective of human trials pre-licensure is to establish the safety and efficacy of a drug or vaccine. These trials are conducted in three phases. Phase I determines the level of toxicity. Phase II determines that it is efficacious and determines the effective minimum dose as in most cases the quantity of drug ingested would determine the side effects as well. Phase III trials are done to learn about the side effects when the drug is used among a larger number of people.

Most drugs are administered for therapeutic reasons; hence the side-effects of the drugs have to be in line with the disease itself. For a serious disease like cancer the very toxic chemotherapy may also give a positive safety profile. However, for vaccines the situation is different as they are given to very large numbers of healthy people and the safety profile demanded has to be carefully assessed.
The statutory rules require that the applicant for New Drugs discovered outside India and approved in the home country should conduct Phase-III trials on not less than 100 patients at three-to-four different hospitals in India to test the efficacy and safety of new drugs for pro-posed indication(s). The basic purpose of such Phase III trials is to determine if there are any ethnic differences that can alter the metabolism, efficacy and safety of the drug when adminis-tered to patients of different ethnicities living in India (such as Indo-Aryans, Dravidians, Mongo-loids, Tribals etc.). Hence, testing drugs as well as vaccines in the Indian ethnic groups is of paramount importance before approving any drug of foreign origin except that in the case of vaccines trials are conducted on thousands of volunteers.

The Standing Committee found that a total of 33 new drugs were approved in the period January 2008 to October 2010 without conduc-ting clinical trials on Indian patients; hence, there was no scientific evidence to show that these 33 drugs were really effective and safe in Indian patients. (See boxes 1 and 2, page 28)
Under the rules, the DCGI has the power to approve drugs without clinical trials in “Public Interest†, though what constitutes public interest is not explained. Finding the reasons provided for waiving trials to be specious, the Committee questioned: “How can approvals given to foreign drugs without testing on Indians be in Public Interest? Some of the reasons given for irregular approvals are: ‘Serious disease’ (all the more reason to conduct clinical trials to ensure that patients in India really benefit from such imported, exorbitantly expensive drugs), ’Rare disease status according to United States Food and Drugs Administration’ (How can the USFDA decide which is rare disease in India?), ‘Orphan drug status in Europe and the USA’ (There is no provision in Indian laws to give special treatment to such foreign drugs).â€

Another explanation offered for approving foreign drugs without clinical trials in the country was: “Most of the drugs are approved in other countries based on multinational clinical trials…. on various ethnic/racial populations†implying that Indians would be included and hence conducting trials in India was not necessary. However, this presumptive remark is not accompanied by any evidence, the Standing Committee observed. The interest is in those ethnicities that live in India, not Slavs, Cauca-sians, Hispanics and Negroes.

Recognising the diversity of the Indian population, home to different ethnicities, the Standing Committee was categorical in stating that pre-approval clinical trials must cover the major ethnic groups. Trials done in just a few centres do not produce any useful data and merely serve to complete the formality of documentation. Taking this issue a step further, the Standing Committee recommended that taking into account the size of our population and the enormous diversity of ethnic groups there is an urgent need to increase the minimum number of subjects that ought to be included in Phase III pre-approval clinical trials, and increase the number of sites so as to ensure a truly representative sample to determine safety and efficacy of New Drugs before marketing permission is granted.

Lapses in the case of HPV vaccines in assessment and trials before licensing

Gardasil and Cervarix, were licensed in India without any Phase-III trials to assess their efficacy and safety in the Indian population.

The multinational clinical trials done with Gardasil and Cervarix did not include ethnic populations living in India. In fact, when the Indian Council of Medical Research signed the much-publicised MoU with MSD, the Indian subsidiary of Merck (manufacturer of Gardasil) in 2005, Gardasil was still an investigational product. A news item about the MoU stated “the vaccine that has been developed by Merck will be tried on 30 to 40,000 women in two phases. The volunteers will be between 17 and 18 years of age. While the first phase will take two years, the second will take four years to complete and the cost of the trials is estimated to be around $ 45 million. The Indian trials will be carried out to see if it’s safe and equally efficacious for women in a tropical country.†1 (Emphasis added)

There was also no emergency to license the two HPV vaccines, other than to hastily create a market for them in developing countries. Though it is true that cervical cancer is the second most common cancer among women in India, cervical cancer deaths are not significant in the country’s overall disease burden. In 2005, deaths due to all cancers (cervical cancer is just one of them) accounted for seven per cent of all deaths in India.2

Besides, cervical cancer has never merited any priority among public health initiatives and programmes, which have limited resources and these vaccines are the most expensive vaccines developed.

The annual report of the Ministry of health and family welfare states: “Up till now we have had no policy for intervention with regard to non-communicable diseases barring giving some limited financial assistance for purchasing of equipment or undertaking pilot projects or studies. Recently, a National Programme for the Control of Cancer, Vascular Diseases and Diabetes, Health Care of Elderly (Geriatrics Care) and Mental Health have been approved to be taken up in 100 districts during the next two years (2010-11 and 2011-12).†3

Merck and GlaxoSmithKline, each, did only one limited phase III trial with their respective vaccines before being granted marketing approval by the DCGI. These trials were immunobridging studies, which merely test whether the immune response in Indian girls is comparable to girls tested in other countries. The duration of these studies was a mere seven months, that is, six months to complete the vaccination schedule and just one month of follow up observation. This was obviously too short a time to assess efficacy or safety of the vaccines.
But even here, Merck’s study was done in four centres in Bangalore, two in Mumbai and one in Pune. Given that only a total of 110 girls were recruited in the study, it is impossible to conclude that girls of different ethnicities were covered.

GlaxoSmithKline’s study was done in four centres, namely, New Delhi, Chandigarh, Kolkata and Mumbai. Even here, it is impossible to conclude that girls of different ethnicities were covered.

However, in the licensing of Gardasil and Cervarix, some novel anomalies came to light.

• Cervarix was approved for use among 10-45 year olds, but it was tested only among 18-35 year olds (in 174 subjects for immune response only). They had not tested their vaccine on a single Indian child till then.

• Gardasil was approved for use among 9-26 year olds, but it was tested only among 9-15 year olds (in 110 subjects for immune response only).

• On July 1, 2009, without any data, the DCGI extended the eligible age-group for Gardasil to include women up to 45 years of age.

The adventurism of the Indian authorities can be judged from the fact that such an exten-sion was refused thrice by the USFDA (Home country Regulatory Authority). Not only this, the USFDA asked Merck to modify the Product Information to include that Gardasil has not been demonstrated to prevent HPV-related CIN 2/3 or worse in women older than 26 years of age. (CIN 2/3 are stages of precancerous lesions),
While decisions were taken on the basis of sketchy and improper data, and the mistakes were compounded by going against home country decisions, trials with Gardasil or Cervarix did not stop here.

Post-licensing, in 2009 the DCGI approved three more trials with HPV vaccines.

• A Phase III trial with Gardasil (Tolerability and Immunogenicity of Gardasil in Females Between 16 and 23 Years of Age in India): This trial was to test efficacy and safety of Gardasil and was to be done on 600 women over a period of 36 months. According to the Y Schedule in the Drugs and Cosmetics Act, this trial on adults should have preceded the trial on 110 girls and it should definitely have preceded the licensing of Gardasil. Why was this trial not concluded before licensing the vaccine and permitting trials on children? Dr Katoch, DG, ICMR, admitted before the Parliamentary Standing Committee on Health and Family Welfare in 2011 that conducting trials on children without conducting them first on adults was a violation.

• A large multicentric trial with Gardasil, involving 20,000 girls aged 10-18 years, with a duration of five years [Trial of Two Versus Three Doses of Human Papillomavirus (HPV) Vaccine in India]: This was labelled as a Phase IV trial (meaning post marketing) whereas the dose of a drug/vaccine is deter-mined in a Phase II trial. Why was the vac-cine licensed for use if the dose was yet to be determined? Normally, dose determination is done with a smaller number of trial sub-jects. In this case if two doses are sufficient then not only lakhs of girls who have been vaccinated with the currently approved three-dose schedule have been overdosed but another ten thousand will suffer overdosing due to the study itself. Alternately, if three doses are required, 10,000 girls will not get even the limited protection that the vaccine can offer as they would have received an insufficient dose.

• A Phase III Clinical Trial to Study the Immunogenicity, Tolerability, and Manufacturing Consistency of V503 (A Human Papilloma-virus [HPV] L1 Virus-Like Particle [VLP] Vaccine that guards against 8 strains of HPV) in Preadolescents and Adolescents (9 to 15 Year Olds) with a Comparison to Young Women (16 to 26 Year Olds): If a multivalent vaccine was already in phase III of testing then why approve a limited vaccine particu-larly when there was no medical emergency? This trial was again done with children in contravention of the Drugs and Cosmetics Act that states clearly that trials with children should be done only after trials with adults have been carried out.

Both these vaccines are recombinant vaccines and in respect of recombinant vaccines ICMR’s Ethical Guidelines on Bio-Medical Research clearly state
“The risks associated with vaccines produced by recombinant DNA techniques are not completely known. However, for all the recombinant vaccines/ products the Guidelines issued by the Department of Biotechnology should be strictly followed.â€
Residual DNA poses a risk of infectivity, tumorogenicity and carcinogenicity.
As recently as March 2012, an application made to the Department of Bio-technology tried to find out whether any of the concerned agencies or companies had sought any advice or clearances in respect of the two vaccines. On this crucial matter the Drugs Controller had failed to seek expert opinion. Another RTI application was filed before the DCGI seeking to know the allowable limits of rDNA and insect cells (these are used to manufacture Cervarix) for vaccines. Instead of supplying the standards, the DCGI office forwarded the application to Government testing laboratories saying that these standards will be only known to the labs and not a concern of the DCGI.

This revelation is shocking because despite purifying processes some remnants of DNA are left in the vaccine—good, bad or otherwise—without setting standards for permissible residue, it is not clear as to how a regulatory authority could give licence for marketing these recombinant vaccines.

In Pursuit of Markets

The Committee found that some manufacturers advertise prescription drugs (Schedule H drugs) in the lay press. Based on incomplete information, patients tend to self-medicate more so because such medicines are generally available without prescription. Such practices can adversely impact not only the health of individuals but even communities and countries. For example misuse of antibiotics can lead to bacterial resistance with serious consequences for public health. The Committee asked the Ministry to take appropriate action against the companies that have advertised Schedule H drugs in the lay press.

In India, The Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954 controls the advertisement of drugs. The Committee observed that the provisions of this Act were not stringent enough, with the result that manufacturers violated them at will. It recommended that apart from giving sharper teeth to the Drugs and Magic Remedies Act, a provision should also be incorporated in the Drugs and Cosmetics Rules to ban such practices and penalize offenders and inform the Standing Committee of action taken.

The Drugs and Magic Remedies Act also contains a list of “Diseases and Ailments (by whatever Name described) which a Drug may not Purport to Prevent or Cure or Make Claims to Prevent or Cure†. Cancer is one of them.

In direct contravention of this law, the manufacturers of HPV vaccines launched a media blitz. The advertising was totally misleading as these vaccines were projected as vaccines against cervical cancer as opposed to vaccines against HPV infection. The advertise-ments hyped the risk of cervical cancer. Though they were aimed at the paying segment of the market, undifferentiated rate of cervical cancer (which has been identified as a disease of poverty) was used to instill fear. No information was provided on the limitations of the vaccines and the ads of GlaxoSmithKline were purported to be issued in pubic interest whereas it stood to profit from any sales generated as a conse-quence because of its profit sharing arrangement with Merck. Huge half page ads ran in national dailies, on TV and hoardings also came up. These were allowed to run for several months before being banned by the DCGI following protests.

It is well documented that Pharma companies take the help of associations of doctors to promote their products. In other countries, this can take the form of substantial payments to the doctors for speaking engagements. In India, the Federation of Obstetricians and Gynecolo-gists endorsed the HPV vaccines and Glaxo SmithKline rewarded them by sponsoring their annual report. The Indian Society for Paediatrics also endorsed the two products. The moves were unwarranted because there was no Indian data and little global data to base such recommendations on. What was ironic is that when the DCGI extended the eligible age group for Gardasil to 45 years, the Indian Society for Paediatrics also endorsed the new age group. Obviously considerations other than altruism were guiding it.
Various city chapters of the FOGSI held meetings to make other doctors aware of the product in the guise of seminars on cancer cervix. All such events are sponsored by Pharma companies any way.

The behaviour of doctors was further modified by the companies by giving them huge discounts on purchases. Some doctors went to the extent of holding camps and offering early bird discounts to women coming forward for vaccination. This sales route is questionable because the patient is at the losing end and has to pay a high price for the same product. The doctor is a no more just treating the patient but is directly benefiting from a dubious approach to preventing the disease.
Pediatricians really went overboard. Instead of limiting themselves to advising their patients and parents, they started to promote the vaccines to young mothers accompanying small children.

The companies did not stop at this but started holding workshops in elite schools. These workshops were targeting minors who would then pressurise their parents. Parents were also sent on a guilt trip for not acting fast enough through direct advertising. Promotions in schools were not limited to workshops but school authorities were also asked to recommend the vaccines for their students.
The companies left no stone unturned. As soon as the vaccines were approved, efforts were started to push them into the national immunisation programme of the country. The manufacturers kept paying lip service to subsidising the cost of these prohibitively expensive vaccines (Rs 9000 for three doses) for the public sector of developing countries. However, an actual decision in this regard has not been taken by them so far.

But in reality the medical representatives started approaching the NRHM functionaries at State and district level for direct purchases. There is evidence of their having approached the State Government of Himachal Pradesh and the Municipal authorities of Mumbai. The country is large and probably one would not know how far they succeeded but there are news reports that the Government of Assam bought vaccines worth Rs 600 million for vaccinating one lakh girls.

Violations in Conditions of Licensing

Post-marketing Surveillance

In the case of drugs and vaccines approved by the DCGI in “public interest†without conducting clinical trials, the marketing approval is conditional to the companies submitting post-marketing surveillance data. Such data is crucial and critical in detecting adverse effects among users.

The Standing Committee sought information on Post-marketing surveillance data for 42 randomly selected new drugs; however, the ministry could provide data for only 8 drugs. In addition, very few periodic safety update reports (PSURs) were India-specific.

So once the licence is granted the companies do not feel any necessity to comply with the post marketing studies. It is well known that even in developed countries, with good spontaneous reporting systems, certain hazards come to light only when post marketing studies are conducted with thousands of patients.

Taking strong exception to such rampant violation of the mandatory requirements, the Committee was of the firm view that there is a poor follow-up of side effects in Indian patients both by doctors and manufacturers. In its view, the infrastructure and system required to pick up adverse effects in India is lacking. The CDSCO has acknowledged that under a World Bank funded programme (23-11-2004 to 30-6-2008) to detect side effects, not a single new adverse drug reaction was reported from anywhere in the country. The Committee felt that the conventional system of locating side effects through spontaneous reporting by doctors to either drug companies or drug regulators was unsatisfactory. The most effective system was by controlled post-marketing Phase IV studies on a very large number of patients.

HPV Vaccines Follow Suit

In the case of the two HPV vaccines also the DCGI had specifically asked for post marketing studies to be carried out by the two companies. Both Merck and GlaxoSmithKline have not carried out a post marketing study with Gardasil and Cervarix, respectively. While the MSD has not made the matters clear and is engaged in a Phase III study with adult women, GlaxoSmithKline has refused to carry out a study in India and has asked the DCGI to accept global PSURs in lieu of the study. Besides, the PSURs submitted by them are not India specific.

Updation of Product Information

The Standing Committee noted that based on inputs from drug regulatory authorities in different countries rapid changes are taking place in the dosage, safety, efficacy and precautions of currently approved drugs leading to alterations in authorised monographs (prescribing information and safety guidelines).

To protect patients, it is vital that approved prescribing information is updated and amen-ded as soon as new information is received. Accordingly, the Committee asked the Ministry to give details of changes in the prescribing information on drugs sold in India in the year 2009 and 2010. In response the Ministry sub-mitted a list of just 14 products, that too only from MNCs. During the same period WHO in its publicly available Bulletin gave information on changes in 274 medicines while the USFDA and British MHRA ordered changes in over 500 drugs.

One of the conditions while approving drugs is the obligation on the part of manufacturers to intimate all changes in efficacy, safety, dosage, side effects etc. that may take place globally. Apparently manufacturers are not submitting such vital information to the CDSCO in violation of rules and continue to use outdated information in their promotion, label, package insert etc. Naturally patients are suffering. The CDSCO also failed in its statutory duty of enforcing laws and penalising those who did not comply with rules on updation of information.

HPV Vaccine Product Information hides Crucial Information

The prescribing Information for Gardasil (in India) does not mention Gardasil has not been demonstrated to prevent HPV-related CIN 2/3 or worse in women older than 26 years of age.

Similarly, the prescribing information of Cervarix (in India) does not mention “Each dose may also contain residual amounts of insect cell and viral protein (<40 ng) and bacterial cell protein (<150 ng) from the manufacturing process†.

Information is being deliberately concealed from the consumer, and potential risks are being downplayed. They are not being told that these are recombinant vaccines, produced through genetic engineering.

In India, there is no mandatory provision of providing information to consumers by way of a product information leaflet. The Committee firmly believed it was absolutely essential to provide accurate information on drugs to patients so that they could be used safely.

Conclusion

The string of violations narrated in the case of the two HPV vaccines are not isolated incidents. The reality of the CDSCO functioning, as amply pointed out by the Standing Committee, is such that all Indians are at great risk. There are many more approved drugs in the Indian market that are irrational, found hazardous and banned in other countries.

There is then an urgent need to weed out a large number of drugs and enforce post-licensure studies in India.

Studies done elsewhere cannot predict how Indians are reacting to various drugs. Even in the case of the two HPV vaccines that underwent sketchy trials we find that data such as immediate injection site reaction, fever and headache are very different in India when compared to the global data.

It is disappointing to note that the response of the Health Minister has been one of side stepping this report and taking a path of least resistance by setting up another committee. This committee is going to just look at improving the functioning of the CDSCO and not into the deeds of omission and commission that are putting the lives and health of Indians in danger.

The Standing Committee has recommended punitive action against officials who have aided the Pharma companies to flood the Indian market with dubious products and stated in no uncertain terms that in the short term there is no way to overhaul the CDSCO. Further, it has said: “In a resource constrained country like India, it is extremely difficult to meet the demands, however, genuine, of all the State entities in full. Hence, prioritisation is the key. For example, work relating to an application for Marketing Approval of a New Drug that will be used by millions and thus have an impact on the well being of public at large in India for years to come, is far more important and urgent than giving permission to a foreign company to conduct clinical trials on an untested new patented, monopoly drug.â€
The need of the hour is to go through the entire lot of drugs approved in the past ten years where the anomalies outlined in the report lie and in the case of life saving drugs, order the necessary studies and updation relying on other vigilant regulatory authorities till Indian data is available. For all other drugs and vaccines, approved without proper trials and scrutiny, licence needs to be suspended till Indian data is made available.

In respect of the two HPV vaccines, as far back as April 2010, the issue was raised in the Parliamentary Standing Committee on Health and Family Welfare and the committee had concluded that:

“the matter of allowing trial of the vaccine as also the approval for its marketing in the country to be enquired into by a premier investigating agency and to take further appropriate follow-up action in the matter.â€

However, the Ministry bypassed the entire issue of licensing and set up an enquiry committee to look into irregularities with just one trial. And though it has been more than a year since the enquiry committee submitted its report, the Minister is yet to take action on the basis of the report.

The Standing Committee has said the mission of the CDSCO has to be that of safeguarding public health—let’s not settle for anything less.

Footnotes

1. Merck, ICMR to conduct joint trials on cervical cancer vaccine, 23-12-2005

http://xn—ihq53mvv6b.bio-medicine.org/medicine-news/Merck—ICMR-to-conduct-joint-trials-on-cervical-cancer-vaccine-6457-1/

2. http://www.searo.who.int/LinkFiles/WHO_Country_ Cooperation_Strategy_India_Health_Development_Challenges.pdf

3. Annual Report to the People, Ministry of Health and Family Welfare, GOI http://mohfw.nic.in/WriteReadData/l892s/9457038092AnnualReporthealth.pdf

The authors are activists in the women’s movement and working on health related issues.