FDA & Ban of Breast Implants: Struggle Anaplastic Large Cell Lymphoma

Introduction

Allergan plc is an Irish pharmaceutical company that acquires, develops, and markets brand-name drugs. Allergan manufactures a number of different variants of breast implants under their Natrelle brand which includes silicone-filled, saline-filled, textured, and smooth implants. On July 24, 2019, FDA took a bold step and requested Allergan to recall their specific variant of textured breast implants to protect women from Breast Implants- Associated Anaplastic Large Cell Lymphoma (BIA- ALCL), a type of rare cancer associated with these implants. As of July 24, 2019, FDA had received 573 unique reports of this cancer of which 481 are associated with Allergan that including 12 deaths which may be an attributable cause of this cancer. Also, the reports from the FDA suggest a risk of BIA- ALCL is six times higher with Allergan textured implants than with other textured breast implants manufacturer in the US. As a result, Allergan has voluntarily recalled its Biocell textured implants. This basically will help ensure that unused products are removed from suppliers as well as doctor’s sites.

BIA- ALCL is a type of lymphoma and not breast cancer, when an implant is placed inside the body, the body develops a fibrous tissue layer around the implant and this layer is called a capsule. In most cases, BIA- ALCL is found inside this capsule. As per data available on the FDA website, BIA- ALCL is found in patients with textured implants. The major difference between textured and non-textured implants is that textured implants develop scar tissue that helps implants stay in their original place as compared to smooth implants. The current information on hand is very limited and still, there is no strong evidence of BIA- ALCL’s association with textured breast implants. The incidence rate of BIA- ALCL in people with textured implants varies widely from 1 in 3817 patients to 30,000 patients. The symptoms of BIA- ALCL include but are not limited to pain, lumps, swelling, or asymmetry in shape. In most cases, these symptoms were seen years after the implants were placed. This event gained much traction in the media when two women who underwent breast implant surgery filed a lawsuit against Allergan seeking monetary damages for themselves and other women with the implants for the removal of recalled implants, surgical, monitoring, and diagnostic fees. On the other hand, due to the unavailability of substantial evidence of an association between Allergan implants and BIA- ALCL, Allergan announced on July 30 that they will bear the cost of new implants only and not the surgery.

US FD&C defines an implant as a “device that is placed into a surgically or naturally formed cavity of the human body and is intended to remain there for a period of 30 days or more.” For any device manufacturer, in order to ensure the safety and efficacy of the device and avoid any post-market recalls, each and every phase of the development cycle becomes crucial i.e. product development, non-clinical trials, clinical trials, and post-market surveillance. Almost all devices fall under the regulation of the FDA either that is a class II device: moderate risk device– which is cleared for marketing through premarket notification 510(k) & GMP submission gateway upon demonstration of “substantial equivalence” or class III device: higher risk device- which is cleared for marketing through premarket approval- PMA process upon reasonable demonstration of safety and efficacy. In order to provide the supporting data to gain the permission to market these devices, they go under a number of non-clinical tests (tests conducted on animals and/or bench), subsequently clinical trials (tests conducted on humans) as per guidance documents published by regulatory bodies and national/ international standards. This data is submitted to and reviewed by the FDA to approve market authorization. The clinical trial is the most crucial stage in the process of launching the product into the market and getting regulatory approval. There are considerable regulations that govern the clinical trials which ensure that the safety, welfare, and rights of the subjects participating are protected and substantial safety and efficacy data are collected at the end. The overall objective of the clinical trials is to establish a product that is safe and effective, and the benefit associated outweighs the risk.

The process of conducting clinical trials is mainly divided into three phases. Phase I studies are performed to assess the safety of the device which spans over several months. It is carried out on healthy volunteers (20 to 100) who are generally compensated to take the part in studies. The study is designed to examine how the drug is absorbed, metabolized, and excreted. It also examines the effects associated with increased dosage levels. While in Phase II efficacy of a drug is tested which can span from several months to 2 years. This study involves several hundred patients and often these studies are blinded that is some patients are given an “experimental” drug while some receive a “control” drug which is the standard treatment. This allows investigators to provide the pharmaceutical companies and FDA with comparative information. Phase III studies involve random and blind testing on several hundred to thousands of people and can last up to several years. The main purpose of these studies is to provide the pharma company and FDA with a thorough understanding of the effectiveness of the product. As it was exhibited in Case study: 6 Bad to the Bone, the poorly designed clinical and non-clinical studies aren’t going to generate substantial and credible data and could result in extreme legal consequences for the company. Some of the major regulations violated by Synthes include; 21 CFR 812.5: Labelling of the investigational device. Synthes were directly involved in off-label marketing, 21 CFR 812.7:Synthes explicitly mentioned/ promoted their product as substantially equivalent (effective & safe) for use to the surgeons without even getting the approval from FDA, 21 CFR 812.150: Reports: In some cases, Synthes didn’t even care to report a certain number of deaths in the clinical studies.

After the completion of clinical trials, the company can request FDA approval for marketing the drug. Clinical trials need to be conducted in accordance with Good Clinical Practices (GCP). GCP is an international ethical and scientific quality standard that provides guidelines to design, conduct and reporting trial that involves human subjects. The harmonized document for GCP is developed by ICH E6, its main goal is to ensure the rights, safety, and well-being of subjects involved in trials and ensure data collected during the study is credible. As it was found in Case Study: 8 (To be Human), black men were recruited to participate in the study in exchange for meager benefits that included some compensation and the cost of covering the funeral. This was totally against the ethics and no information was provided on risks associated with the syphilis study whatsoever. This was an eye-opening event that led to the development of 21 CFR 50 (Protection of human subjects was developed). The principles of GCP have been incorporated in a number of regulations in the US as well as EU such as directive 2001/20/EC, 2005/28/EC in the EU. While in the US similar regulations are developed as that of the EU. However, there is some unique aspect of US regulations. The first aspect is the Investigational New Drug (IND) Application through which the pharma company obtains approval to initiate clinical trials. The broad categories of IND include preclinical testing, manufacturing info, investigator information, and clinical trials protocols. Institutional Review Board (IRB) protects the rights and welfare of human subjects involved in the study, IRB is appointed by the sponsor which is almost equivalent to Independent Ethics Committees (IEC) in the EU.

After the rigorous process of successful completion of non-clinical and clinical studies, the final step is to present and submit all the data in a comprehensible manner to FDA for obtaining the marketing authorization of the product. FDA subjects this data to a thorough review process and ensures the quality, safety, and efficacy of the drug and that there is not any undue risk associated with the product. As was seen during Case study 11: Data doesn’t lie, completion of Phase III studies and submission of clinical and non-clinical studies data to the FDA doesn’t ensure approval from FDA. The approval process also depends on a number external factors. For example, a drug-coated balloon (DCB) was likely responsible for a number of deaths and BD submitted a similar device under the same pathway. Since the previous similar device was under investigation and substantial evidence of it causing the deaths was still to be found, the FDA asked BD to submit more supporting data for their below-the-knee PAD device. Despite these rigorous regulations placed on products before they reach the market, it is not all the time possible to ensure the product in the market is risk-free. For example, in this case, Allergan textured implants were potentially identified to cause BIA- ALCL after certain years the patient was operated. Thus, market vigilance becomes necessary for a manufacturer as well as FDA to monitor any adverse safety-related issue that was not evident before the commercialization and which enables it to take appropriate action.

FDA has been monitoring this issue since the very first case of BIA- ALCL was reported in 2011 and at the same time, the information of the association between this cancer and textured breast implants was conveyed to the healthcare providers and patients. Since then FDA is working to spread awareness and encourage reporting of all the cases related to BIA- ALCL. Although the FDA doesn’t recommend the removal of implants without BIA- ALCL symptoms due to potential risks, they have provided helpful information to patients and doctors to discuss the next steps. Also, it is still not clear if the issue of BIA- ALCL is associated with certain models of textured implants or all textured breast implants. In the guidelines published by the FDA, they have clearly called out that the risk of BIA- ALCL is greater for the textured implants. In addition to the voluntary recall, FDA is currently working on actions to ensure women who consider breast implants have all the information they need to have to make informed and balanced decisions on the benefits and risks of breast implants. For example, improved labeling of breast implants, which could include a boxed warning and patient decision checklist to help women understand risks and benefits.

Perspective and conclusion

My perspective on the article matches that of the FDA. Here FDA has done a commendable job in following this issue from the very first instance reported in 2011. Also, by recalling certain textured devices from the market upon request by the FDA, Allergan has set forth an excellent example of their commitment to work hand in hand and not against the FDA and strive to protect public safety and rights. Extensive research needs to be conducted in order to establish and explore if there is a relationship between textured implants and its association with BIA- ALCL which will require substantial effort and time. To achieve this, there need to be properly designed clinical studies and a number of different subjects with diverse backgrounds need to be involved in the study. Although this is going to take some time and companies associated with the manufacturing of textured implants would be in dilemma, the ultimate result would benefit the greater population as a whole. FDA is committed to protecting the health of women and providing as much information as possible to ensure they and medical professionals know the benefits and risks of these devices, and that users have the most accurate and complete information to make an informed decision. This voluntary recall is an ultimate result of the FDA’s collaborative efforts to improve the quality of data collected and their ongoing work to evaluate safety information.

References:

1. https://www.allergan.com/.
2. https://www.insider.com/allergan-breast-implants-biocell-linked-cancer-2019-8.
3. https://www.insider.com/breast-implant-cancer-bia-alcl-what-is-it-2019-2.
4. Tobin, J.J. and G. Walsh, Chapter 2: Regulatory Strategy ; Medical Product Regulatory Affairs Pharmaceuticals, Diagnostics, Medical Devices. 2008.
5. Tobin, J.J. and G. Walsh, Chapter 9: Medical Devices; Medical Product Regulatory Affairs Pharmaceuticals, Diagnostics, Medical Devices. 2008.
6. Tobin, J.J. and G. Walsh, Chapter 6: Marketing Authorization; Medical Product Regulatory Affairs Pharmaceuticals, Diagnostics, Medical Devices. 2008.
7. Tobin, J.J. and G. Walsh, Chapter 4: Non-Clinical Studies ; Medical Product Regulatory Affairs Pharmaceuticals, Diagnostics, Medical Devices. 2008.
8. Tobin, J.J. and G. Walsh, Chapter 5: Clinical Trials; Medical Product Regulatory Affairs Pharmaceuticals, Diagnostics, Medical Devices. 2008.
9. 21 CFR PART 50: PROTECTION OF HUMAN SUBJECTS. TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER A--GENERAL.
10. E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER).
11. 21 CFR PART 812: INVESTIGATIONAL DEVICE EXEMPTIONS. TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER H--MEDICAL DEVICES.
12. 21 CFR PART 312: INVESTIGATIONAL NEW DRUG APPLICATION. TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER D--DRUGS FOR HUMAN USE.
13. 21 CFR PART 56: INSTITUTIONAL REVIEW BOARDS. TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER A--GENERAL.
14. 21 CFR PART 54: FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS. TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER A--GENERAL.
15. Tobin, J.J. and G. Walsh, Chapter 12: Oversight and Vigilance; Medical Product Regulatory Affairs Pharmaceuticals, Diagnostics, Medical Devices. 2008.