The Approval Process for Biosimilars

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was signed into law in March 2010 as part of the Affordable Care Act. The BPCI Act created an abbreviated approval process for biosimilars, the goal of which is to demonstrate “biosimilarity” between the proposed product and the original product, not to independently establish the safety and effectiveness of the proposed product.

A “totality of the evidence” approach is taken by the FDA in evaluating biosimilars for approval. The results from clinical trials are important, but data from “preclinical” work is also considered.

Once a biosimilar is approved for use by the FDA, it can be approved for additional indications (conditions) based on a concept called “extrapolation of data.” If the data collected on the biosimilar in preclinical work shows the same clinical result as the original product (the biologic), additional clinical trials do not have to be conducted.

For instance, the clinical trial for the biosimilar filgrastim-sndz studied its effectiveness and safety in a clinical trial whose participants were being treated for breast cancer. When approval was granted by the FDA for filgrastim-sndz, it was as a bone marrow stimulant for the same five indications approved for the original product, filgrastim:

• Patients with cancer receiving myelosuppressive chemotherapy (treatment that stops or slows the growth of blood-forming cells in the bone marrow).
• Patients with acute myeloid leukemia receiving chemotherapy.
• Patients with cancer undergoing bone marrow transplantation.
• Patients undergoing autologous peripheral blood progenitor cell collection and therapy (a method of replacing blood-forming stem cells destroyed by cancer treatment).
• Patients with severe chronic neutropenia (abnormally low count of a type of white blood cell).

Biosimilars Approved by the FDA

Including filgrastim-sndz, there are currently twelve biosimilars approved by the FDA for the treatment of specific conditions.

2016 and 2017

In 2016 and 2017, the FDA approved six immunosuppresant drugs for the treatment of certain forms of arthritis, psoriasis, ulcerative colitis and Crohn’s disease. These drugs, listed in the order of their approval, are:

• Infliximab-dyyb (Inflectra); the original product is infliximab (Remicade).
• Etanercept-szzs (Erelzi); the original product is etanercept (Enbrel).
• Adalimumab-atto (Amjevita); the original product is adalimumab (Humira).
• Infliximab-abda (Renflexis); the original product is infliximab (Remicade).
• Adalimumab-adbm (Cyltezo); the original product is adalimumab (Humira).
• Infliximab-qbtx (Ixifi); the original product is infliximab (Remicade).

In September 2017, the FDA approved bevacizumab-awwb (Mvasi) for the treatment of five types of cancer:

• Non-squamous non-small cell lung cancer (NSCLC)
• Metastatic colorectal cancer (mCRC)
• Glioblastoma
• Metastatic renal cell carcinoma
• Persistent, recurrent or metastatic carcinoma of the cervix

Bevacizumab-awwb is approved for the same indications as the original drug, bevacizumab (Avastin) and could reach the U.S. market as soon as 2020, after the patent on bevacizumab expires.

In December 2017, the FDA approved trastuzumab-dkst (Ogivri) for the treatment of people with HER2-positive breast cancer or HER2-positive gastric cancer. HER2 is a growth-promoting protein found on the surface of some cancer cells. The original drug is trastuzumab (Herceptin); its patent expires in 2019.

2018

In May 2018, the FDA approved epoetin alfa-epbx (Retacrit), a biosimilar to epoetin alfa (Epogen, Procrit). Epoetin alfa-epbx is designed to reduce or avoid the need for red blood cell transfusions when treating anemia caused by chronic kidney disease or chemotherapy.

In June 2018, the FDA approved pegfilgrastim-jmdb (Fulphila), a biosimilar to pegfilgrastim (Neulasta) to decrease the chance of infection in people being treated with chemotherapy for certain types of cancer. Pegfilgrastim-jmdb, like pegfilgrastim, is a bone marrow stimulant that can help the body make white blood cells.

All cancer treatments can cause side effects. It’s important that you report any side effects that you experience to your health care team so they can help you manage them. Report them right away—don’t wait for your next appointment. Doing so will improve your quality of life and allow you to stick with your treatment plan.

There are certain side effects that may occur across different treatment approaches. Following are tips and guidance for managing these side effects.

Digestive Tract Symptoms

Nausea and vomiting

• Avoid food with strong odors, as well as overly sweet, greasy, fried, or highly seasoned food.
• Eat meals cold or at room temperature, which often makes food more easily tolerated.
• Nibble on dry crackers or toast. These bland foods are easy on the stomach.
• Having something in your stomach when you take medication may help ease nausea.

Diarrhea

• Drink plenty of water. Ask your doctor about using drinks such as Gatorade which provide electrolytes as well as liquid. Electrolytes are body salts that must stay in balance for cells to work properly.
• Over-the-counter medicines such as loperamide (Imodium A-D and others) and prescription drugs are available for diarrhea but should be used only if necessary. If the diarrhea is bad enough that you need medicine, discuss it with your doctor or nurse.
• Choose foods that contain soluble fiber—for example beans, oat cereals, oranges, and flaxseeds. High-pectin foods such as peaches, apples, oranges, grapefruit, bananas, and apricots can also help to avoid diarrhea.
• Avoid foods high in refined sugar and those sweetened with sugar alcohols such as sorbitol and mannitol.

Loss of appetite

• To help maintain your weight, eat small meals throughout the day. That’s an easy way to take in more protein and calories. Try to include protein in every meal.
• To keep from feeling full early, avoid liquids with meals or take only small sips (unless you need liquids to help swallow). Drink most of your liquids between meals.
• Be as physically active as you can. Sometimes, taking a short walk an hour or so before meals can help you feel hungry. *Keep high-calorie, high-protein snacks on hand such as hard-boiled eggs, peanut butter, cheese, ice cream, granola bars, liquid nutritional supplements, puddings, nuts, canned tuna, or trail mix.
• If you are struggling to maintain your appetite, talk to your health care team about whether appetite-building medication could be right for you.

Managing Fatigue

Fatigue (extreme tiredness not helped by sleep) is one of the most common side effects of many cancer treatments. If you are taking a medication, your doctor may lower the dose of the drug, as long as it does not make the treatment less effective. If you are experiencing fatigue, talk to your doctor about whether taking a smaller dose is right for you.

There are a number of other tips for reducing fatigue:

• Take several short naps or breaks.
• Take short walks or do some light exercise, if possible.
• Try easier or shorter versions of the activities you enjoy.
• Ask your family or friends to help you with tasks you find difficult or tiring.

There are also prescription medications that may help, such as modafinil. Your health care team can provide guidance on whether medication is the right approach for your individual circumstances.

Managing Pain

There are a number of options for pain relief, including prescription and over-the-counter medications. It’s important to talk to a member of your health care team before taking any over-the-counter medication to determine if they are safe and to make sure they will not interfere with your treatments. Many pain medications can lead to constipation, which may make your pain worse. Your doctor can prescribe medications that help to avoid constipation.

Physical therapy, acupuncture, and massage may also be of help in managing your pain. Consult with a member of your health care team before beginning any of these activities.

Bone Loss

Some therapies can cause bone loss, which increases the risk for osteoporosis (a condition in which bones become weak and brittle, leading to a higher risk of fracture). Talk with your health care team about how exercise and changes in your diet may help keep your bones healthy.

It’s also important to talk to your doctor about the medications available for bone health:

• Bisphosphonates such as zoledronic acid (Zometa and others) slow the process by which bone wears away and breaks down. These medications belong to a class of drugs called osteoclast inhibitors.
• RANK ligand inhibitors block a factor in bone development known as RANK ligand, which stimulates cells that break bone down. By blocking RANK ligand, these drugs increase bone density and strength. So far, the only drug approved in this class is denosumab (Xgeva, Prolia). Like bisphosphonates, RANK ligand inhibitors are a type of osteoclast inhibitor.

Frequently Asked Questions

Q. What is bioequivalence and how does it relate to the FDA’s approval of generics and biosimilars?

A. Bioequivalence is the primary factor in the FDA’s approval of generic (chemical-based) drugs. It means that the generic drug delivers the same amount of active ingredient(s) to the targeted cancer cells as does the original brand-name drug. Although the approval process of biosimilars differs from that of generics, clinical trials must prove bioequivalence—that the biosimilar has no clinically meaningful difference when compared to the original biologic drug.

Q. Does Medicare cover biosimilars?

A. Each Medicare Prescription Drug Plan has its own list of covered drugs (called a formulary). If the original drug (the biologic) is covered under the formulary of the drug plan, the biosimilar will also be covered. This is because the biosimilar has been approved by the FDA for the same indication(s) as the biologic; additionally, a biosimilar is generally less expensive than the biologic.

Q. Are the side effects for biosimilars the same as for the original biologic

A. As biologics and biosimilars are bioequivalent, sharing the same efficacy (effectiveness) and safety profile, the potential side effects are the same or very similar.

Q. I am being treated with a biologic therapy. If a biosimilar becomes available, will I be automatically placed on it??

A. Standard medical practice is for your doctor to discuss the potential move from any biologic drug to its biosimilar; there would not be an automatic change. However, a change should be strongly considered, as biosimilars are as effective as the original biologic drug, have the same safety profile and may be considerably less expensive.