Drug Approval Process – Risk Mitigation

by Anastasia Malicka

The practice of medicine advanced significantly with the discoveries of new treatments. Our life expectancy increased by 10 years since1965 due to our advancements in medicine. Influenza that killed more Americans in 1918 than all of the battles fought during the World War 1 is now effectively controlled. Pharmacological treatments for many other disease states such as heart disease, diabetes, immunodeficiency, neurodegenerative disorders, and cancer are now helping people to live a longer and more productive life.

However, there are risks associated with the use of any new and/or existing medication, primary since each person is unique and reacts differently to chemical or biologic compounds. In addition, the disease progresses differently among individuals making it difficult to assess all of the potential complications. It is also due to the fact that most people suffer from more than one condition which could elevate risks. Regardless of technology, we will not likely eliminate all of the risks; however, we can get better at early detection and prevention of serious, life-threatening events.

The pharmaceutical industry is one of the most regulated industries in the world, but regardless of increases in regulations and oversight, it will not completely mitigate all of the risks associated with the introduction of new drugs. The public needs to feel secure that all of the necessary steps were taken to prevent any obvious risks that could be detected and prevented. It also requires an unbiased oversight to protect the public from potential exposure to harmful products and enforce their appropriate use. That is the primary responsibility of the FDA.

Currently, FDA regulates about a quarter of the United States economy. FDA is the oldest consumer protection agency in the U.S federal government. Its origin can be traced back to 1848 with the appointment of Lewis Caleb Beck into the Patent Office. The present function of the FDA did not begin until the passage of the 1906 Pure Food and Drugs Act, prohibiting the marketing of adulterated and misbranded food and drugs. It was in response to the Elixir of sulfanilamide tragic incident that caused over one-hundred deaths. In 1938, Congress passed the law that governs our current food and drug regulations (the Food, Drug, and Cosmetic Act – FDAC).

FDA function and responsibility evolved over the years, imposing new rules and guidelines. Again, the primary responsibility of the FDA is to protect our public from harmful products. Some of the most significant changes included:

• Strict inspection and regulations of clinical trials designs imposed in 1977.
• The Food and Drug Modernization Act (FDAMA) of 1997 significantly expanding the FDA’s authority over drug regulations.
• Generic Drug User Fee Amendment (GDUFA) of 2012 allowing generic companies to pay the FDA when they apply for approval of a generic version of the drug.

FDA is currently an agency that resides within the Department of Health and Human Services (DHHS). It consists of the Office of the Commissioner and four directorates overseeing the core functions of the agency: Medical Products and Tobacco, Foods, Global Regulatory Operations and Policy, and Operations. FDA's primary responsibility is to maintain public health (Source: FDA Website). It provides strict guidelines and regulates the approval and marketing of new products. No product can be promoted in the United States unless it receives formal FDA approval. The agency also regulates all of the promotional activities, including review of promotional materials and conducting audits.

The Discovery process of new chemical or biological compounds that could potentially result in new pharmacological treatment is a very complex and expensive process. It generally starts with a screening of millions of potential compounds before identifying one that offers clinical benefit.

The time and cost associated with developing new drugs vary, depending on the complexity of the disease intended to be treated. It also depends on the experience level of the scientists, medical investigators, and commercial teams dedicated to supporting the development and commercialization of the new drug.

In most cases, companies receive 20 years of patent protection for the new chemical entity. The developmental process can take 10 years or more, leaving the company with only limited time to market its product. Patent protection is the biggest determining factor in whether the company will decide to invest in the development of the new product. 

Generic manufactures can erode 80% of the branded product’s business within the first 6 months of the introduction of their generic version of the branded product. Patent protection rights were recent changes and now generic companies can challenge the manufacture’s patent as early as 5 years of receiving the approval, significantly shorting marketing effectors of the company that invested billions in the development of the new product (Generic Drug User Fee Amendment of 2012).

The change in patent protection rights will have a significant impact on future discoveries of new treatments, especially relating to the management of chronic conditions such as diabetes and CV disease that require a substantial developmental cost. Therefore, a lot of developmental efforts are now focusing on rear disease states, affecting less than 200,000 people in the United States, but can secure Orphan Drug approval status, significantly extending its patent protection rights.

FDA regulates the entire drug development process starting from Phase I through post-marketing trials, referred to as Phase IV clinical trials, and promotional practices of pharmaceutical products. It includes formal submissions and negotiations relating to clinical trials design and labeling claims, as well as other means which can include risk management program mandates (REMs). After the launch is can conduct on-site practice and manufacturing inspections, audits which could lead to other restrictions such as corporate integrity agreement (CIA) imposed by the Office of the Inspector General.

It not only regulates promotional efforts associated with pharmaceutical products that could lead to market withdrawal, but it also targets companies’ executives, making them financially liable, even if they didn’t do anything wrong (Source: Melissa Maleske, September 2012 Inside Counsel). In addition, employees also assume personal liability, and any misconduct, either intended or in error, can potentially lead to imprisonment, financial liability, and disbarment from the industry.

The company might be also excluded from participating in federal programs (Medicare, Medicaid, VA hospitals and clinics, etc.) which is a ‘virtual death sentence” since it blocks pharma companies from at least 30-40% of the market. This also prevents people, especially the elderly, poor, and veterans, from getting the right medications since they receive federal medical converge and/or aid. Therefore, it can be extremely damaging to both the manufactures as well as patients needing appropriate medications, compromising their treatment outcomes.

Consequently, the industry adopted a very strict training program, in addition to already comprehensive compliance training requirements that each employee was responsible to complete on an annual and/or semi-annual basis. It is currently mandatory training and condition of employment in most pharmaceutical and biotechnology companies. Regardless of the comprehensive training, mistakes can happen, and they are extremely damaging.

Any pharmaceutical company or academic institution initiating Phase I clinical trial must submit an investigational new drug (IND) application to FDA for approval at least 30 days before commencing any trials. The submission includes a detailed study protocol, outlining the trial design, enrollment criteria, and analysis that will be conducted. Once approved, FDA requires that all involved in conducting trials must adhere to federal regulations governing the protection of trial participants, referred to as the “common-sense” rule. The primary purpose of common-sense rule:

1. Ensure that the risks of participants are reasonable in relation to the likely benefits and the importance of the data collected.
2. Requires voluntary, informed consent from participants.

In addition, Institutional Review Board (IRB) conducts an independent review of research to make sure trials are following protocols and participants remain safe.

Phase I trials involve a small number of participants (20-80) to test the safety and tolerability of the new compound. Dose-ranging studies are also conducted to determine the maximum and minimum tolerated dose. Development of the new compound is continued only if the results from Phase I trials proved to be safe for human consumption, otherwise, the program is terminated. Close to 65% of new compounds proved to be safe in Phase I and continue to Phase II. However, there is less than 11% likelihood that the product will receive the final approval, mostly due to failure to demonstrate efficacy benefits in subsequent clinical trials. (Source: Michael Hay, David W. Thomas, Jesse Rosenthal, Cecilia Economides, John L. Craighead, Biomed Tracker, Biotechnology Industry Organization, 2012).

Phase II clinical trials involve a greater number of people and multiple locations. It is during this phase that the drug’s efficacy primary end-point is being investigated, in addition to its safety and side effects. Historically it generally followed a double-blind, placebo-controlled protocol. However, due to high financial pressures to demonstrate value over existing treatments, more trials include active control groups that generally represent standard treatments. This design is most risky and costly to the company sponsoring clinical investigations however it provides a greater chance of securing reimbursement if it demonstrates superiority in efficacy or side effects over existing treatments. In Europe, this is a mandatory requirement for any new product to receive reimbursement.

Phase III clinical trials involve a much larger number of patients. In addition to evaluation of safety, tolerability, and primary efficacy end-point measures, it typically includes additional secondary efficacy data such as outcome measures like productivity, Quality of Life, and Activities of Daily Living measures. It typically takes anywhere from 6-8 years to get to Phase III clinical-stage, therefore the primary goal is to increase the likelihood to secure FDA approval.

At the end of the Phase III trial, if the product proves to be efficacious and safe, the company conducting the trials submits a new drug application (NDA) to the FDA containing all of the evidence from clinical trials. The level of documentation of all clinical investigations is extensive. The agency has to review each document and evidence, which requires tremendous manpower and time. It takes anywhere from 6 to 16 months for the agency to review all of the evidence and provide a final decision.

Prior to providing the final decision, FDA conducts an Advisory Panel which includes key opinion leaders specialized in that specific disease state for which the product was being investigated. It is available to the public via life broadcast. Generally, if the Advisory Panel provides positive feedback, the product receives FDA “approval” letter. However, FDA may require additional data and/or may require the company to conduct more trials. In this case, the FDA issues an “approvable” letter. This is generally not favorable, since the company has only 5-10 years to market the product and any additional trials will significantly shorten its commercial success. Therefore, many products that receive “approvable” letters are discontinued due to high risk and limited commercial viability.

When FDA issues an “approval” letter, the company can begin promoting the product on its approved label and can submit the data to payers to initiate contracting negotiations.  This phase is generally very focused on getting this product to the market as quickly as possible and initiate promotional activities.

All of the promotional materials have to be in strict compliance with the approved label. Unfortunately, many patients’ outcome data that is being measured during Phase III clinical trials are restricted from being shared with health care professionals and patients, preventing them from access to truthful and scientifically accurate data detailing real-life benefits of the drug. The fair balance must include all of the side effects and adverse events, and typically is much more detailed and lengthier than the actual statements with the benefit of the drug. This is typically why many physicians try to stay away from prescribing new products since they do not want to assume any liabilities. This dynamic substantially slows new product adoption, and lately, it is much more pronounced than historically.    

Regarding direct-to-consumer (DTC) advertising, the industry developed its own best industry guidelines that would allow doctors to learn about the product first before going directly to their patients. Lately, there is limited investment in DTC due to its high cost and most of the promotional efforts involve social media instead of TV or print advertising.

Despite the heavy focus on commercialization of the new product after receiving FDA approval, there is still additional research that is being conducted. It can involve Phase IV trials that look at different population segments, efficacy end-points, and potential new indications. The product may also be approved with the requirement to offer a risk management program (REMs). Most of the biologic compound requires REMs since they are associated with higher risks and patients require close monitoring. In addition, companies are conducting on-going surveillance of patients receiving their products. It requires regular reporting to FDA the list and extends of any adverse events and side effects, most of which have to be submitted to the FDA within 7 days if it is life-threatening.

Despite all of the analytical rigor and strict FDA regulations, it did not eliminate the entire risk associated with the introduction of a new drug to the market. First, the exposure of the product is much greater than in clinical trials. Second, it is not possible to control the actual use of the product, especially as it related to contraindications and restrictions relating to co-morbid conditions which may not be known to some patients. Third, genetics and life-style differences can trigger adverse events that would be impossible to detect in a well-controlled environment. Therefore, despite all of the efforts to secure the safe use of pharmaceutical products, we will not be able to completely remove all of the risks associated with the introduction of new products. The emphasis has to be placed on providing necessary support and education to prescribing physicians to make appropriate treatment decisions based on strong evidence and help them select appropriate patients. It is also important to continually educate patients and the public on the seriousness of the medications and empower them to make an educated decision.

There is a tremendous danger that if our regulations restrict people from obtaining truthful and scientifically valid information, and if they restrict the access of the medication to the group of patients that need it the most, the entire system will be crippled. As with any fair balance and disclaimer, there is also a great need for transparency and trust in people’s ability to make appropriate choices. That is the greatest future challenge for our industry and regulatory bodies to make sure we protect the public from harm; however, we accomplish it without compromising their constitutional rights.  

References:

1. Steven J. Williams and Paul R. Torrens (2008). Introduction to Health Services, 7th Edition: Delmar Publishers.
2. Leiyu Shi and Douglas A. Singh (2013). Essentials of the U.S. Health Care System, 3rd edition: Boston: Jones and Bartlett Publishers.
3. Gerald Masoudi and Christopher Pruitt (2011). The Food and Drug Administration v. the first amendment: A survey of recent FDA enforcement: Journal of Law-Medicine: Health Matrix.
4. Jamie L. Aldes (2008). The FDA Clinical Trials Process: Effectuating Change in the Regulatory Framework Governing Clinical Trials to Account for the Historical Shift from “Traditional” to “New” Phase I Trials: Journal of Law-Medicine: Health Matrix.
5. Melisa Maleske (September 2012): Bitter Pill: Corporate Crime: Inside Counsel.
6. Jim Frederick (February 2013): FDA: new user fee program to speed generic approval process: Drug Store News: Lebhar-Friedman Inc.
7. Michael Hay, David W. Thomas, Celia Economides, John L. Craighead, Jesse Rosenthal (2012): BioMedTracker, Sagient Research Systems, San Diego, CA: Biotechnology Industry Organization (BIO), Washington, DC: Human Genome Sciences, Rockville, MD: Biotechnology Industry Organization.