21 October 2015

The controversy over biosimilars: what’s the deal?

Drugs Government TheHill

Politicians deserve either a brickbat or bouquet over their IP stubborness. You decide.

It took two days, but the Australian government has claimed a victory in negotiations on the Trans-Pacific Partnership by not compromising the length of intellectual property protection for biologics.

The battle was waged over how long drug companies should be able to monopolise the market before facing competition from inexpensive generics.

“This point kept the negotiations going for an extra two days, but we were very, very clear, extremely clear about our position at the outset and we remain consistent right through,” Prime Minister Malcolm Turnbull said in an interview with 3AW presenter Neil Mitchell.

Despite pressure from the United States, Trade Minister Andrew Robb said he drew a “red line” at prolonging Australia’s current five year data exclusivity period to 12 years.

While data exclusivity and patents are two separate types of intellectual property that rely on different information, both grant monopoly rights to the holder, Generic and Biosimilar Medicines Association CEO Belinda Wood explains.

Patents are granted on an invention, in this case the molecule itself, whereas data exclusion protects the clinical trial data that is submitted to regulators in order to gain regulatory approval. In Australia, generic companies are unable to use the data from that originator package for five years – effectively keeping them out of the market for that period.

US biologic companies argue that they need a 12 to 15 year period of market exclusivity to recoup the costs of developing biologics, and ensure ongoing innovation.

But biologics are expensive, and each year a cheaper biosimilar is kept out of the hands of consumers comes at a substantial cost to the PBS and consumers. Biologics, which include monoclonal antibodies and vaccines, are a new wave of medications that are used to treat conditions like diabetes, rheumatoid arthritis, cancers, Crohn’s disease, anaemia, low white blood cell counts and skin conditions such as psoriasis.

Wood wouldn’t go so far as to call the preservation of a five year period a ‘win’, but she did say it would have been a blow to extend it any longer. A change would have just provided an additional monopoly to the patent holder, Wood said.

“There’s no evidence anywhere to show that increasing data exclusivity encourages innovation

“There’s no evidence anywhere to show that increasing data exclusivity encourages innovation, and clearly the Australian government wasn’t convinced by that argument either.

“Pressure from the US to extend Australia’s current five-year data exclusivity period in the TPP would only delay market access for generic and biosimilar medicines, unnecessarily delay the realisation of savings to the PBS and delay patient access to affordable medicines,” Ms Wood said.

The issue of biosimilars is topical right now because we are in the midst of a “patent cliff ” that has seen dozens of big-seller products come off patent, and a growing market share in biologic medicines.

It’s a “very exciting” time for generics and biosimilars, according to Wood, with a lot of interest from companies bringing products to the market.

By 2019, biologics are expected to be worth more than $220 billion in the global market, according to a 2013 Biologics and Biosimilars World Markets report. At the moment biologics make up half of the top 10 drugs on the PBS, and Health Minister Sussan Ley has said their proportion of total PBS spending has risen from around 4% to 25% in the past decade.

Given that the introduction of a biosimilar or bioequivalent drug to the PBS forces a 16% price drop on the originator drug, the introduction of biosimilars offers serious savings in a time of anxiety around healthcare spending.

And without a PBS subsidy, patients are looking at costs between $400 and $1700 per treatment, according to the health department.

WHAT DO YOU NEED TO KNOW ABOUT BIOSIMILARS?

Biosimilars are often thought of as the generic version of innovator biologic medicines, but that’s not quite true. For generics to be approved for market, manufacturers have to prove the bioequivalence of the new medicine with the innovator formulation.

As the FDA explains, this means that generics “have the same active ingredient, and are the same as those brand name drugs in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use”.

In contrast, biosimilars, also known as follow on biologics or Similar Biological Medicinal Products (SBMP), can’t make the claim of bioequivalence. Biologics, also known as large-molecule drugs, are derived from organic sources.

They are made up of proteins, sugars, nucleic acids or combinations thereof, or cells and tissues. They also have a complex structure, and any small variation in the manufacturing process can create subtle differences in the end product.

While small molecule drugs, which are chemically synthesised, have a more uniform and predictable structure, it’s going to be a harder challenge for biosimilars to prove they are up to standard.

So for a product to qualify as a biosimilar with the regulatory body, it has to demonstrate that it is similar enough in safety and efficacy, and biological, immunological and physicochemical characteristics.

In August, the first monoclonal antibody biosimilar was registered in Australia, infliximab (Inflectra, Hospira) was recommended for inclusion under the PBS and allowed to be substituted at the pharmacy-level. The TGA approved it for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, adult and paediatric Crohn’s disease, adult and paediatric ulcerative colitis and plaque psoriasis.

The PBAC outcomes report from July outlined two randomised clinical trials in which “no difference in efficacy, safety or immunogenicity” was found from switching from the originator REMICADE to biosimilar INFLECTRA.

“There is evidence from three randomised clinical trials in treatment-naïve patients initiating on either INFLECTRA or REMICADE that support a finding that Inflectra has equivalent effectiveness and equivalent safety compared to REMICADE,” it said.

CONTROVERSY

This variation has been at the heart of a huge controversy around PBAC’s decision to allow substitution of biosimilars with biologics at the pharmacy-level.

In a world-first, PBAC announced in July it would have a default approach of allowing biosimilars the same substitution rules as generics. The announcement was made as part of a PBS reform package, projected to save the PBS $880 million over five years.

Giving biosimilars an ‘a-flag’ means that, like generics, pharmacists could swap the patient’s medicines from the brand-name to the biosimilar, and back, without clinician input.

The PBAC announced that this ‘a-flagging’ will be applied in the “absence of data to suggest significant differences in clinical effectiveness or safety”.

But medicines and specialist groups are worried. The Australian Rheumatology Association’s president, Dr Mona Marabani, expressed her “serious concerns” over the potential for patient safety to be compromised.

She said that evidence on the safety of multiple switching was “sparse” and that an absence of evidence was no evidence of absence.

In her June submission to PBAC, Dr Marabani expressed concerns that variations between the original and the biosimilar have the potential to lead to the immune system treating the drug in a different way, known as immunogenicity.

This may render them less effective or even harmful. “For example a minor change in manufacturing of the biologic erythropoietin a decade ago led to a sharp increase in an incurable form of severe antibody-induced anaemia. It took years to determine and address the cause,” she wrote.

Addressing the Senate, Dr Marabani said that nobody knows what happens if substitution is permitted at the pharmacy level on multiple occasions.

It also raises medico-legal questions, she noted.

“If switching at the pharmacy is permitted, what happens if something goes wrong? How will the pharmacovigilance be managed? If people are being swapped from month to month, from prescription to prescription without their doctor knowing, how will it be possible to know which agent is to blame if there is a problem?” Dr Marabani said.

This safety concern was summed up by the Alliance for Safe Biologic Medicines, a biotech lobby group, in their submission to PBAC: “Unlike chemical medicines, the greater size, complexity and sensitivity of biologics means that they cannot be copied exactly.

A reverse-engineered biosimilar medicine from a different cell line designed to mimic the therapeutic properties of its reference biologic medicine can only ever be ‘similar’ to that product, never the same.

“Even seemingly minor production differences can produce unexpected effects, including unwanted immune responses that may harm rather than heal. We know that patient responses can vary with chemical medications and expect the same to be true with biologic ones.

“However, given the chronicity and seriousness of the diseases these medications are designed to treat, we believe there is less margin for error and recommend a slower and more conservative approach to substitution until more is known about these medications.”

The PBAC acknowledged that a “great majority” of submissions expressed concern about pharmacy level substitution, but sought to reassure groups that the decision was still ultimately in the hands of the patient and the doctor.

But it stressed that any doctor who is concerned about the potential of substitution has the power to prevent it, by ticking the ‘no substitution’ box on the prescription, as they can do with other drugs.

In preparation for the more widespread introduction of biosimilars, the federal government has earmarked $20 million for an education package to improve awareness and confidence in the drugs.

Biosimilars in Oz
Biosimilars currently approved by the
TGA include:
• Insulin glargine for diabetes
• Infliximab for some autoimmune disorders
• Filgrastim for cancer, haematopoietic stem cell transplantation, neutropenia
• Somatropin for growth disturbance due to chronic renal insufficiency, pituitary dwarfism, Turner syndrome
• Epoetin lambda for anaemia, cancer, chronic kidney failure

BIOSIMILARS WITHOUT BORDERS

Prime Minister Malcolm Turnbull has promised the TPP won’t lead to a price hike on any Australian medicines, calling these fears “unfounded” in his joint press release with the trade minister.

In the 3AW interview, Mr Turnbull said the TPP wouldn’t impact on the PBS or to any other part of the health system. “This deal… is not going to make drugs more expensive in Australia whatsoever. Our position is that we have a very good regime which both rewards innovation for companies that develop new drugs and need to have a period of exclusivity, and also encourages competition. We believe we have the balance right and that has been accepted in this agreement with other eleven countries that make up the TPP.”

The 12 TPP member countries, which include Australia, Brunei Darussalam, Canada, Chile, Japan, Malaysia, Mexico, Peru, New Zealand, Singapore, the United States and Vietnam, make up 40% of global GDP.

These member countries were on the receiving end of $109 billion in goods and services from Australia last year. But while Australian politicians are patting themselves on the back about their TPP agreement, the TPP faced criticism from Médecins Sans Frontières.

In a statement on October 5, the group expressed their “dismay” at member groups agreeing to the terms which they argued would unnecessarily extend monopolies and delay price-lowering competition. They say that the TPP will go down in history “as the worst trade agreement for access to medicines in developing countries, which will be forced to change their laws to incorporate abusive intellectual property protections for pharmaceutical companies”.

MSF rails against the agreement, which will see all developing member countries adhering to the biologic protection, saying “the negative impact of the TPP on public health will be enormous, be felt for years to come”.

Closer to home, another point of contention was the inclusion of Investor-State Dispute Settlement (ISDS) clauses in the agreements. These provisions would enable foreign investors to sue governments if their investments have been harmed, such as tobacco companies suing over plain packaging laws.

Trade Minister Andrew Robb says that caveats have been introduced to protect the government in the case of plain packaging on cigarettes and other public health issue from companies seeking to sue.

But there is concern that this may not be enough.

Shadow minister for trade and investment, Senator Penny Wong, is concerned that the safeguards introduced won’t be strong enough to stand up against litigious multinational corporations seeking to pursue law suits against the government.