The cervical cancer vaccine you had to fly to Hong Kong for is finally coming to the mainland — 20 questions you may want answered

This vaccine changed the way patients and researchers face cancer, that "modern plague." These 20 questions tell the story behind it.

GlaxoSmithKline (GSK), Britain's largest drugmaker, announced this morning that its cervical cancer vaccine, the HPV shot Cervarix, has cleared its market application with the China Food and Drug Administration (CFDA), and will formally go on sale early next year.

It is the first HPV vaccine brand approved for market in China. The vaccine first reached the market in 2006 and is now sold in 160 countries and regions. Even where it has yet to arrive, people want it badly — it is the world's only cancer vaccine. No other cancer has a preventive treatment proven safe and effective. You could say it changed the way patients and researchers face cancer, that "modern plague."

GSK's Cervarix targets two big viral strains, HPV 16 and HPV 18. It is approved for women aged 9 to 25 and requires three doses in a row. Last year Reuters reported that the vaccine would give a big lift to GSK's China revenue in 2016.

For the past few years the press has followed every step of the HPV vaccine trials that GSK and Merck (MSD), the two big drugmakers, have been running in China. According to an earlier report in Southern Weekly, under China's current rules for judging vaccine efficacy, trials of this kind of vaccine usually need tens of thousands of participants from different regions before they yield useful results.

But GSK said today that it had run six years of clinical trials in China for this product, with only a little over 6,000 subjects across the vaccinated and control groups. The company stressed that the vaccine still offers strong protection against certain cervical diseases linked to cancer-causing HPV strains, in line with the data from its global studies.

The new vaccine may end up inside the public health system, as it already is in some countries. Hervé Gisserot, GSK's senior vice president and general manager for pharmaceuticals and vaccines in China and Hong Kong, told reporters that by working with the relevant government departments, the company would explore "innovative pricing approaches" on the mainland to support adding Cervarix to the national immunization program.

Here are 20 questions worth asking about the disease and the vaccine.

1. What are cervical cancer and HPV?

Like every other disease filed under the word "cancer," cervical cancer is cell division gone out of control — in this case, a common malignant tumor of the cervix. In the 1970s the German scientist Harald zur Hausen found its cause: a virus called human papillomavirus, or HPV. Since then doctors have broadly agreed that 99% of cervical cancer cases are linked to HPV infection.

The cancer is common in women. China's 2015 cancer statistics report showed that among cancers unique to women, breast cancer ranks first and cervical cancer second, and that patients are getting younger. China recorded an estimated 98,900 new cervical cancer cases and 30,500 deaths in 2015; counting the people who never get screened or treated, the real number of patients is almost certainly higher. When Anita Mui died of cervical cancer in 2003, the disease drew a great deal of attention.

2. How was the vaccine developed? Can it prevent cervical cancer every time?

What makes the cervical cancer vaccine unusual is that it is the world's only cancer vaccine. No other cancer has a preventive treatment proven safe and effective.

Two of the world's big drugmakers have brought cervical cancer vaccines to market since 2006. That year Merck developed the first HPV vaccine anywhere, Gardasil, which won priority review and went on sale in the United States. GSK followed with a bivalent vaccine, Cervarix.

Broadly, the vaccine cuts the chance of developing cervical cancer by 70%. Qiao Youlin, who heads the epidemiology research office at the Cancer Institute of the Chinese Academy of Medical Sciences, told Caixin that although there are more than a hundred HPV strains, about 70% of cervical cancers worldwide are caused by just two of them, types 16 and 18 — and the vaccine is 99% effective against both, with protection that may last as long as 20 years.

That is why the World Health Organization calls cervical cancer the cancer most likely to be prevented and controlled.

3. How long does it take a vaccine to go from the lab to the market to the people who need it?

As we noted in an earlier report on GSK, developing a new drug is an enormously complicated business: target drugs, lead compounds, several phases of clinical trials, the market application. At every stage you need several times — sometimes dozens of times — as many half-finished candidates waiting in reserve. By the journal Nature's reckoning, a single new drug that finally reaches the market represents an average of 13.5 years of work and as much as $1.78 billion in research spending.

Even after a launch, winning over the market takes a long time. According to Science and Technology Daily, 30% of new drugs still cannot be sold in a single province two years after launch; only 25% of approved new drugs make it into one to five provinces; and in the first year more than half never enter the normal sales system at all.

As for GSK's suggestion that Cervarix "may be added to the national immunization program," China revises its national medical insurance catalogue roughly every four or five years, and the last revision was in 2009 — so if the timing lines up, it is indeed possible.

4. Why is there a best time to get the HPV vaccine?

The United States and the World Health Organization currently put the age range for HPV vaccine protection at 9 to 26, with 11 to 12 the ideal age. The course is three injections within six months.

Why the hurry? Gong Xiaoming, a former obstetrics and gynecology doctor at Peking Union Medical College Hospital, explained that the HPV vaccine prevents infection but cannot treat it. Sex is not the only way HPV spreads, but once a person starts having sex, infection is common — and the vaccine is worth much less after that.

5. Why did Hong Kong's Department of Health push the age limit past 45?

As research on the HPV vaccine has gone on, the ages it covers have widened. Hong Kong's Department of Health raised the age limit for the quadrivalent vaccine to 45 back in 2010, saying large clinical studies had shown it protects women aged 24 to 45 well. Australia did something similar, and the FDA has also extended the vaccine's approved age range to 45.

6. Which countries can get the HPV vaccine, and how fast and how widely have they taken it up?

Since the HPV vaccine appeared in 2006, it has gone on sale in more than 160 countries and regions, Japan and Hong Kong among them.

Caixin reports that Merck filed marketing applications for Gardasil in a number of countries in 2006. Europe, Australia, New Zealand and Hong Kong, Macau and Taiwan all approved it. GSK's cervical cancer vaccine appeared the same year, and within 12 months 80 countries, including the United States, Britain and Canada, had approved its use.

7. Is the HPV vaccine arriving late in China?

It took the HPV vaccine 10 years to win an import licence for the Chinese mainland market — later than in Europe, the United States and several neighboring countries and regions.

According to a paper in the journal Vaccine by Dr. Wang Shaoming of the Cancer Institute at the Chinese Academy of Medical Sciences and Peking Union Medical College, counting only girls and women aged 9 to 15, the seven-year vaccination delay from 2006 to 2012 may have cost 59 million Chinese women and girls of the right age the chance to be vaccinated at home.

8. Why so late?

Mostly because China's approval process for imported vaccines is long. Most countries accept the FDA's decision. China's State Food and Drug Administration, by contrast, required both vaccines to redo their Phase III trials — the ones that mainly test efficacy — before it would issue an "imported drug registration certificate." Southern Weekly reports that under the rules, once a vaccine's trials end, the drug administration convenes experts to review it, and that review runs anywhere from one to five years depending on the drug.

China is not the only country that insists on local trials for imported vaccines; India and Japan do too. But for the HPV vaccine both India and Japan used the endpoint the WHO recommends, persistent infection — meaning that if a vaccine can be shown to cut the rate of persistent infection, it can be judged to cut precancerous lesions and cervical cancer as well. That shortened the trials and got the vaccines to market quickly. China's drug administration set its endpoint at actual cancer, or cervical intraepithelial neoplasia of grade 2 or higher.

Some people outside medicine argue the wait was worth it. Liu Peng, an associate professor of public administration at Renmin University of China, told Southern Weekly in an earlier interview that drug review has to weigh more than international standards and trial results: it also has to weigh local factors such as the population's genetics, how people take medicine, and how much drug risk they will tolerate. Vaccines, he added, are high-risk drugs, and China's population is large enough that even a low-probability adverse event can affect a lot of people.

Siddhartha Mukherjee, a cancer physician at Columbia University Medical Center and an associate professor at its College of Physicians and Surgeons, argues that the simplest, most direct way for advocates and regulators to reach a compromise is to create more data. He is also the author of The Emperor of All Maladies: A Biography of Cancer. "Creating more data" is exactly the compromise behind the HPV vaccine's late arrival in China.

9. Is it an expensive vaccine? Do developed countries pay for it?

Next to the vaccines most of us know, the HPV shot is not cheap. A Caixin report puts the price of the full three-dose course in Hong Kong at 2,000 to 3,000 yuan. Given the low-price strategy GSK has used on several drugs over the past year, the industry guesses the three doses of Cervarix could come in under 1,000 yuan.

Because of the price and the unknowns that remain, most countries and regions leave vaccination voluntary rather than compulsory. Apart from a few that fold it into free health care, most make people pay themselves. New Express reports that Australia offers the quadrivalent HPV vaccine free to all women aged 12 to 26, and from this year is also vaccinating 800,000 boys aged 12 to 13 free of charge (to prevent genital warts; whether vaccinating men protects women against cervical cancer is still unclear). Italy provides the quadrivalent vaccine free nationwide but does not require it. Germany has put the quadrivalent vaccine into its routine national immunization program. The United States, France, Luxembourg and Norway, among others, "recommend" the vaccine to young women.

10. What kind of company is GSK, and how have its drugs shaped our lives?

GSK is Britain's largest drugmaker, with revenue of £24 billion in fiscal 2015. By revenue it is the world's seventh-largest pharmaceutical company; the top three are Johnson & Johnson, Novartis and Pfizer.

GSK makes most of its money in two fields, vaccines and respiratory drugs. As one of the world's largest vaccine makers, it supplies more than 1.1 billion doses a year to 173 countries; that business brought in £3.7 billion in fiscal 2015. When Ebola broke out, GSK was among the first drugmakers in the world to join the hunt for a vaccine.

11. Is GSK the only company making HPV vaccines? How much money is in it?

Only two drugmakers, GSK and Merck, make HPV vaccines that have been rolled out worldwide. In China, two domestic drugmakers are also developing their own and trying to bring them to market.

According to the pharmaceutical database Menet, Merck's HPV vaccine sales reached $1.907 billion in 2015. GSK's sold respectably at launch, but by 2015 had fallen to just £17 million.

12. Apart from drugmakers, who else is working on HPV diagnosis?

The cervical cancer that HPV causes has to be fought on two fronts at once: prevention and screening.

Since 2003 the Bill & Melinda Gates Foundation has worked with medical institutions around the world to spread a cervical cancer screening method called careHPV. It detects well, works fast (results usually come back in about two and a half hours), needs little equipment (it works without running water or electricity) and is easy to use (a village doctor can run it after brief training), which makes it especially well suited to low-income countries and regions.

13. What worries people most about the HPV vaccine? Is it safe?

For a vaccine with such a short history, what worries people most is safety. On the whole the international view is that the HPV vaccine is fairly safe; the World Health Organization, the U.S. FDA and other bodies endorse and promote it.

But the shot can cause side effects: local redness, swelling and pain, along with whole-body symptoms such as fever, dizziness and nausea. In 2013 more than 30 Japanese women reported pain all over the body after the HPV vaccine that treatment did not relieve, and Japan's Ministry of Health, Labour and Welfare suspended its "active recommendation" of the vaccine, making it purely voluntary.

Cases like these can make people hesitate. But Japan's health ministry also stressed that the decision did not mean the two vaccines were unsafe — it was a temporary step, taken to allow further study and a fuller set of data before a full rollout.

14. Before this, what could mainland residents do if they wanted the vaccine?

Go somewhere that had already approved it, such as Hong Kong or Macau. Since the vaccine takes three injections, the repeated trips added up.

The other group that got to the HPV vaccine early were mainland students studying in Britain, the United States, Australia and elsewhere; some could even claim the cost back through their school's health insurance.

15. When did Hong Kong bring in the vaccine, and how does its version differ from the one just approved on the mainland?

Hong Kong's Department of Health introduced the HPV vaccine across the board in 2006. Because it accepts the FDA's conclusions, the approval paperwork is fairly simple and usually takes about a year; a patient only needs a prescription from a doctor at a qualified hospital to get the shot.

The HPV vaccines now approved for sale in Hong Kong include Merck's quadrivalent Gardasil (covering four HPV strains; the same applies below) and its nine-valent Gardasil 9, plus GSK's bivalent Cervarix — the very vaccine just approved on the mainland. So Hong Kong offers more choices, and the nine-valent Gardasil 9 protects against cervical cancer better.

16. Once the mainland has the vaccine, how many visitors and how much revenue will Hong Kong lose?

Time Weekly emailed Hong Kong's Department of Health about this in early 2016, and the answer then was that it had no figures on how many mainland residents came to Hong Kong for the shot. But by the reckoning of one agent who arranges such trips, if every qualified clinic sees an average of 50 booked patients a day, roughly 5,600 mainland visitors a day come to Hong Kong to be vaccinated.

In 2015 Hong Kong also launched a broad HPV vaccine subsidy scheme, for a vaccine priced at up to HK$3,600 per person; the going rate now is around HK$2,700.

The estimate of how many people come for the shot may be on the high side, but even so the math suggests Hong Kong stands to lose more than HK$1.5 million a day in this line of business.

17. After the vaccine, do you still need regular cervical cancer screening?

Yes. The HPV vaccine cannot prevent cervical cancer every time, because today's vaccines do not cover every cancer-causing strain of the virus — but if an HPV screening comes back negative, you will not need a second one for at least five years.

There is a small story behind cervical cancer screening too. In 1952 Papanicolaou persuaded the National Cancer Institute to launch the largest secondary-prevention clinical trial in the history of cancer, using what is now known as the Pap smear. It is considered the moment cervical cancer turned "from incurable to curable." It also prompted doctors to look for ways of detecting cancer in other organs where it takes hold. And it convinced people that with cancer, that "modern plague," prevention is treatment.

18. Why did GSK beat Merck to the mainland market, and what does that mean for GSK China?

From what GSK and Merck have each said publicly, the two companies handed regulators their clinical data and filed their market applications at almost the same time, and both were held up for the same reason: China demands more proof of vaccine efficacy, and therefore more clinical data.

Merck told QDaily by email that for its flagship HPV product, the quadrivalent Gardasil, the collection and analysis of trial data is now complete, the materials have been submitted for review, and the various registration steps are going smoothly. When it will actually reach the market is still an open question.

Still, finishing first must mean GSK has taken the market's high ground — a study of 79 newly launched drugs by China Pharmaceutical Economic News found that the new drugs that eventually win out are usually performing well by weeks 10 to 12 after launch.

19. Which Chinese companies are working on this kind of vaccine?

At home, Wantai BioPharm, a subsidiary of the Yang Sheng Tang Group, and the listed Walvax Biotechnology are both developing HPV vaccines. Wantai's candidate entered Phase III trials back in 2011, the same stage Merck was at; the company's researchers say that by breaking through foreign patent barriers it can cut production costs substantially.

Worth noting too: Walvax built its HPV program by buying a drugmaker called Shanghai Zerun, and that 2012 acquisition cost 310 million yuan.

20. How much could that bring the price down?

High-priced patented drugs are one of big pharma's great money machines. Once patent protection lapses and generic makers are allowed in, prices usually fall 85% to 90% within a year. Past experience also suggests that once China and India enter the market for a given vaccine, a large price cut tends to follow.