38 Any regulatory r approvals that we receive for our product candidates will be subj u ect to limitations on the approved indicated uses for which the product may be marketed and promoted or to the conditions of approval (including the requirement to implement a REMS), or contain requirements for potentially costly post-marketing testing. We will be required to report certain adverse reactions and production problems, if any, to the FDA, EMA and comparable foreign regulatory r authorities. Any new legislation addressing drug r safety issues could result in delays in product development or commercialization, or increased costs to assure compliance. The FDA and other agencies, including the Department of Justice, closely regulate and monitor the post-approval marketing and promotion of products to ensure that they are manufac f tured, marketed and distributed only for the approved indications and in accordance with the provisions of the approved labe a ling. We will have to comply with requirements concerning advertising and promotion for our products. Promotional communications with respect to prescription drugs r are subj u ect to a variety of legal and regulatory r restrictions and must be consistent with the information in the product’s approved labe a l. As such, we may not promote our products for indications or uses for which they do not have approval. The holder of an approved BLA or MAA must subm u it new or suppl u emental applications and obtain approval for certain changes to the approved product, product labe a ling or manufact f ur t ing process. We could also be asked to conduct post-marketing clinical trials to verify the safety and effi f cacy of our products in general or in specific patient subs u ets. If original marketing approval was obtained via the accelerated approval pathway, we could be required to conduct a successful f post-marketing clinical trial to confir f m clinical benefit for our products. An unsuccessful f post-marketing study t or failure to complete such a study t could result in the withdrawal of marketing approval. If a regulatory r agency discovers previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, or problems with the facility where the product is manufact f ur t ed, or disagrees with the promotion, marketing or labe a ling of a product, such regulatory r agency may impose restrictions on that product or us, including requiring withdrawal of the product from the market. If we fail to comply with applicable regulatory r requirements, a regulatory r agency or enforcement authority may, among other things: • issue warning letters that would result in adverse publicity; • impose civil or criminal penalties; • suspend or withdraw regulatory approvals; • suspend any of our on-going clinical trials; • refuse to approve pending applications or suppl u ements to approved applications subm u itted by us; • impose restrictions on our operations, including closing our contract manufact f ur t ers’ facilities; • seize or detain products; or • require a product recall. Any government investigation of alleged violations of law could require us to expend significant time and resources in response and could generate negative publicity. Any failure to comply with on-going regulatory r requirements may significantly and adversely affe f ct our ability to commercialize and generate revenue from our products. If regulatory r sanctions are applied or if regulatory r approval is withdrawn, the value of our company and our operating results will be adversely affe f cted. Health l care legi e sl i at l iv t e measures aime i d at reducing i health l care costst may a have a material adverse r effe f ct on our busine i ss and results of operations. Third-party payors, whether domestic or foreign, or governmental or commercial, are developing increasingly sophisticated methods of controlling healthcare costs. In both the United States and certain international jurisdictions, there have been a number of legislative and regulatory r changes to the health care system that could impact our ability to sell our products profit f ably. In particular, in 2010, the Patient Protection and Affo f rdable Care Act, as amended by the Health Care and Educ d ation Reconciliation Act, or collectively the ACA, was enacted, which, among other things, subj u ected biologic products to potential competition by lower-cost biosimilars, addressed a methodology by which rebates owed by manufac f turers under the Medicaid Drug r Rebate Program are calculated for drugs r that are inhaled, infused, instilled, implanted or inje n cted, increased the minimum Medicaid rebates owed by most manufact f ur t ers under the Medicaid Drug r Rebate Program, extended the Medicaid Drug r Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations, subj u ected manufactur t ers to annual fees and taxes for certain branded prescription drugs r , and provided incentives to programs that increase the federal government’s comparative effe f ctiveness research.