Immunotherapy and Healthcare Compliance

Immunotherapy is the treatment of disease – by suppressing or activating the immune system. Immunotherapies are categorized as activation immunotherapies if the therapies are designed to elicit or enhance an immune response. Immunotherapies are categorized as suppression immunotherapies if the therapies are designed to suppress or reduce an immune response. The primary use of immunotherapies is for the treatment of cancer.

New developments in immunotherapy

According to Harvard Health, the emergency of immunotherapy and certain drugs is being used to supplement the use of chemotherapy to treat cancer. The drugs focus on specific proteins or genes – that are “altered or overexpressed on cancer cells.” Immunotherapy is already helpful for the treatment of lung, bladder, and skin cancers.

“One form of immunotherapy is called an immune checkpoint inhibitor. It takes the brakes off immune cells, unlocking their ability to detect altered proteins on cancer cells in order to attack and kill these cells. These drugs include programmed death (PD-1)-inhibitors and PD-L1-inhibitors (such as pembrolizumab, atezolizumab, nivolumab), and cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors (ipilimumab).”

Harvard Health states that the FDA has approved many of these new drugs – without fully “understanding their effects and side effects” – creating many questions for both physicians and patients. Some of the questions and answers about immune checkpoint inhibitors follow:

Does immunotherapy benefit all patients? Some, but not all, cancer patients will benefit from immunotherapy. Immunotherapy seems to work better for cancers with “higher levels of PD-L1 protein or a massive number of gene mutations due to DNA repair defects.” The research is still evolving though. Researchers are still working to determine which patients will benefit from immunotherapy.

How long does immunotherapy last? Cancer cells do adapt – build up resistance to targeted therapies.

When a tumor responds to immunotherapy, the remission tends to last a long time (a year or more), unlike a response to chemotherapy (weeks or months). Also, with immunotherapy, tumors initially may swell as immune cells engage with the cancer cells, then later shrink as cancer cells die. The early swelling is called psuedoprogression.

What are the side effects involved with immunotherapy? Harvard Health states that immunotherapy, like all drugs, does have some side effects. The side effects of immunotherapy drugs are, according to Harvard Health, as follows:

• Serious side effects.
  • “Immunotherapy with PD1/PD-L1 inhibitors is generally well-tolerated, but serious side effects may occur. This happens in about 20% of people given PD1/PD-L1-inhibitors. It occurs in 40% to 60% of people given a combination of PD1-inhibitor and CTLA4-inhibitor immunotherapies.”
  • The side effects generally start about two to three months after the therapy begins. Physicians should closely monitor a patient’s therapy. Early recognition and prompt responses to side effects can help. Immunotherapy unleashes immune cells. This can cause inflammation in the colon (resulting in diarrhea), the lungs (patients may have shortness of breath and cough), the skin (creating a rash), the liver (causing the liver enzymes in the blood to increase), the thyroid gland, and other parts of the body.
• How are side effects of immunotherapy managed? If the side effects are severe, the physician will stop the immunotherapy and start a treatment of corticosteroids. Patients should consult with their oncologists before self-medicating. “For example, if you have diarrhea, taking loperamide (Imodium) may arrest the symptom. But it won’t address the root cause, which is inflammation of the large intestine. Uncontrolled inflammation of the intestine may lead to rupture of the intestinal wall, which can be life-threatening.”
• Do antibiotics affect how well immunotherapy works? Antibiotics may affect the ability of immunotherapy to kill cancer. Generally, people who take immune checkpoint inhibitors and receive antibiotics – are less likely to benefit from immunotherapy than other patients. Patients should check with their cancer team to discuss the use of antibiotics when there are signs of infection.
• What should physicians and other healthcare professionals understand when a patient is sick? Any patient who seeks medical care at an emergency room or urgent care center should tell the healthcare provider that the patient is taking immunotherapy medications for their cancer treatment, the type of cancer the patient has, what therapies the patient is receiving, and when the patient was examined. The information about the immunotherapy treatments should be kept in the primary care doctor’s records.

The FDA and drug compliance issues

The Federal Food and Drug Administration regulates the development and approval of new drugs. The agency relies on the Center for Drug Evaluation and Research (CDER) to conduct the research to ensure that drugs are safe and effective.

As part of the U.S. Food and Drug Administration (FDA), CDER regulates over-the-counter and prescription drugs, including biological therapeutics, and generic drugs. This work covers more than just medicines. According to FDA, since 1938, every new drug must obtain approval through a New Drug Application before the drug can be placed into commercial use. Drug sponsors use the NDA to obtain formal approval from the FDA to approve a new pharmaceutical for sale and marketing in the U.S.

The aim of the NDA process is to acquire enough information to determine:

• If the drug is “safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.”
• The drug’s proposed labeling is appropriate.
• The “methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.”

The NDA should include the proper documentation explaining the “whole story” of the drug including what happened during the clinical trial; the drug’s ingredients; the results of animal studies; how the drug behaves; and how the drug is manufactured, processed, and packaged.

Seasoned health care compliance lawyers advise drug developers about how the NDA review process works and the resources the FDA considers including “the legal requirements of a new drug application.” The FDA expects that manufacturers will comply with its guidance documents for NDAs. The FDA also establishes “policies intended to achieve consistency in the Agency’s regulatory approach and establish inspection and enforcement procedures.”

The guidelines are not regulations or laws. Alternative uses may be considered if the application complies with the federal Food, Drug, and Cosmetic Act (FD&C), and the applicable regulations.

What types of drug applications does the FDA consider?

The FDA considers the following types of drug applications, some of which will likely apply to the approval of immunotherapy drugs:

• Investigational New Drug (IND). Current federal law:

“Requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA.”

• New Drug Application (NDA).  A sponsor submits an NDA to FDA when the sponsor thinks there is enough evidence about the safety and effectiveness of the drug – to meet FDA’s requirements. “The application must contain data from specific technical viewpoints for review, including chemistry, pharmacology, medical, biopharmaceutics, and statistics. If the NDA is approved, the product may be marketed in the United States.”
• Abbreviated New Drug Application (ANDA). This application to CDER applies to the approval of generic drugs. “Generic drug applications are called “abbreviated” because the applications are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.  Instead, a generic applicant must scientifically demonstrate that its product is bioequivalent (i.e., performs in the same manner as the innovator drug).”
• Biologic License Application (BLA). These products “are approved for marketing under the provisions of the Public Health Service (PHS) Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product.”

There are also FDA requirements for approval of over-the-counter drugs (OTC drugs).

A recent FDA approval of a cancer immunotherapy

Reuters announced on March 18, 2022, that Bristol Myers Squibb stated that the company had received approval for “the first drug in a new class of cancer immunotherapies as an initial treatment for advanced melanoma, the deadliest form of skin cancer.” Bristol Myers Squibb estimated the drug treatment will result in yearly sales of $4 billion.

FDA approved “relatlimab from a class known as LAG-3 inhibitors – short for lymphocyte-activation gene 3 – for use in combination with Bristol’s blockbuster immunotherapy Opdivo as an initial treatment for advanced melanoma.” “Relatlimab, which will be sold under the brand name Opdualag, more than doubled the time it took for advanced melanoma to worsen compared with Opdivo alone in clinical trials, a measure known as progression-free survival.”

The drug is the third cancer immunotherapy drug made by Bristol Myers Squibb that has received approval. The Chief Medical Officer for Bristol Myers Squibb said that Relatlimab will only be used in combination with Opdivo. The CMO said that “LAG-3 inhibitors like relatlimab can reinvigorate the immune system by restoring the function of “exhausted” T cells – a key component of the immune system – which could improve Opdivo’s performance.”

Bristol Myers Squibb expects to charge $27,389 for the combination. The company said Bristol Myers Squibb is testing the drug combination for other types of tumor including colorectal, lung and liver cancer.

HIPAA and immunotherapy

As discussed above, it helps if a patient’s health information regarding their cancer and immunotherapy treatments is shared with other health providers. Any time health information is shared, there is a concern that the sharing of the information may violate the Health Insurance Portability and Accountability Act of 1996 (HIPAA)

HIPAA is a federal law enacted to ensure the privacy of patient information from disclosures without the patient’s consent or knowledge. The US Department of Health and Human Services (HHS) issued the HIPAA Privacy Rule to implement the requirements of HIPAA. Another rule, the HIPAA Security Rule protects a subset of the information protected by the Privacy Rule.

HIPAA’s Privacy Rule governs “protected health information” by entities covered by the rule. Any covered entities must comply with the rule which ensures that the patient’s health information is protected while also allowing information that is needed to provide quality healthcare to be accessible.

Covered entities generally include healthcare providers who send electronic health information in connection with benefit eligibility inquiries, claims, referral authorization requests, and other covered transactions. Other covered entities include insurance plans, HMOs, Medicare, Medicaid, some long-term care insurers, healthcare clearinghouses, and “business associates.”

Covered entities may be able to disclose protected health information, without an individual’s authorization, for certain reasons our skilled healthcare lawyers can explain. Otherwise, written consent from the patient is required.

Stark and the Anti-Kickback Statute and Immunotherapy

Drug manufacturers and physicians need to comply with Stark Law and the AKS which regulate when and how referrals can be made.

The good news is that immunotherapy treatments are being developed with the reasonable hope that the drugs will help patients with different types of cancer. These new drugs must have FDA approval before the drugs can be marketed. Manufacturers and medical practices must comply with Stark Law and the AKS. Medical practices must also comply with HIPAA.

Pharmaceutical companies and physicians should contact Cohen Healthcare Law Group, PC to review the healthcare compliance issues for immunotherapy treatments. Our experienced healthcare attorneys help healthcare companies and providers understand their federal and state compliance issues.