The Regulatory Debate Around Pre-approval Product Access

When it comes to pre-approval access of investigational products, varying stakeholders are offering their opinions on what they feel is best. Competent authorities must balance both the potential goods for society and the potential goods of individual patients. Similarly, manufacturers must balance the needs of their business with individual patient desires. This produces the ethical dilemma of those in control of the products of choosing between “the good” and “the good.” In the past, information was not as fluid and transparent to patients. However, patients and their advocates have more information available to them than ever before on experimental new therapies. Of course, that information may be incomplete-the data may be proprietary, embargoed or simply not yet exist. The information may also be tainted with rhetoric designed for other purposes, whether political, competitive or otherwise. Nevertheless, patients and their advocates are asking new questions. This results in the need for a revalidation and/or rethinking of the existing regulatory system.  

The FDA tries to strike the balance, and/or accomplish the goods of society and the individual patient through its evolving expanded access program. This program, under certain conditions and criteria, gives patients access to investigational products not approved for marketing. Over the decades, various advocacy groups have challenged the need for FDA’s involvement at all in this process,¹ especially for patients to which there is no other marketed product to address their illness. One of those groups of late is the Goldwater Institute, which has successfully inspired over half of the U.S. states to pass “Right to Try” laws. Advocates for Right to Try tout that once a state law is passed that the FDA is not needed in the decision to give access of certain products to those with terminal illnesses. Naturally, despite the model legislation put forth by the Institute, each state has installed their own requirements and conditions² in their version. This generally results in no two states being alike in their requirements and conditions for access under Right to Try. The coexistence of federal and state laws, especially when directly challenging the constitutional authority of a 100-year-old federal agency, does not go without its criticisms. 

There are also various initiatives by Congress that attempt to resolve the early access issue. Assuming there is agreement that 1) those that are near death with a terminal illness have a different risk/benefit paradigm than those not in that situation (e.g., long-term side effects, short-term side effects or possibly even a chance of death from the drug may be insignificant to these individuals, as without the treatment, death is determined certain anyway); and 2) we don’t want to return to the days of “buyer-beware” and “snake oil peddlers.” The U.S., as a society, is called to reevaluate the existing balance of making the best decisions between special allowances “for the one” while trying to protect and advance “the many.” 

Expanded access program summary

The history of the FDA’s evolving stance of early access since the program’s inception is well documented. In 2009, the revision of regulations brought more organization to its activities and differentiated its expanded access into essentially three categories: 1) expanded access for individual patients³; 2) expanded access for intermediate-sized populations⁴; and 3) expanded access for widespread treatment.⁵ The kinds of products generally available under expanded access are listed in Table 1.⁶

The process for expanded access is relatively straightforward. When a physician and individual patient desire to use a product under expanded access, the typical step is to first contact the manufacturer and see if it will make the product available, and if so, under what terms. Parameters such as product availability, cost, data collection requirements and others are important in this decision. An additional key regulatory component is to assure that FDA law and regulations are adhered to when administering the product outside of the scope of an investigational new drug (IND) obtained for clinical trials. Should the manufacturer have an intermediate-sized population or a widespread expanded access IND in place for which the patient meets the criteria, then the manufacturer can ship the product under that IND. Alternatively, if the product is under a clinical trials IND to which the patient does not qualify, the sponsor can add a protocol under the existing clinical trials IND for that patient. If, however, no such IND exists, then absent applying for one of those, the individual patient expanded access IND approval would be sought. 

Although not required, it is common for manufacturers to not want to sponsor individual patient INDs and, instead, push that obligation onto the treating physician. When the treating physician undertakes the obligation of a sponsor in these cases, they are the person responsible for completing the initial and ongoing paperwork with the FDA pursuant to the IND. As an IND requires submitting large amounts of information about the product that the physician does not have, the manufacturer is free to allow the physician to cross-reference its clinical trials IND. This provides the FDA with the product information without the need for the sponsoring physician to replicate or duplicate it. The physician gives the FDA a Letter of Authority from the manufacturer to cross-reference their IND(s) so that the FDA has record of this permission.⁷ Thus, most information gathered and presented to the FDA by the physician is about the patient and his or her need.

The most current related event occurred in June 2016 when the FDA finalized three guidance documents pertaining to its expanded access program. The first, “Individual Patient Expanded Access Applications: Form FDA 3926,” makes final the draft form published in February 2015, which can be used by physicians for individual-level access of investigational drugs.⁸ This new form gives physicians their own document to use for individual patient access instead of requiring the same form that the manufacturers need (Form 1571) for their IND. Like the ballyhooed original “100-hour form” (which the physician’s time actually ranged more like one⁹  to eight¹⁰  hours to complete), this form is estimated as a “45-minute form,” and also seems will take less time to complete. Much of the form is requesting demographic information that can be filled out by an administrative person. The other two guidance documents are self-explanatory in nature: “Expanded Access to Investigational Drugs for Treatment Use- Questions and Answers” and “Charging for Investigational Drugs Under an IND- Questions and Answers.” In addition to these three guidance documents, the FDA has also published two fact sheets answering basic questions about expanded access, which can be distributed to physicians and patients, respectively.

Is FDA an ‘obstacle’ in expanded access?

Much of the critique of FDA’s expanded access program is misplaced. To point out any issues with expanded access, one must appropriately distinguish between the time and resources required for full marketing approval versus the process by which terminally ill patients can seek an exception for expanded access. Critics of the full drug approval process often cite the expense private industry must undertake to develop a drug and achieve FDA approval or clearance (usually quoting between $1.3 billion¹¹ and $2.6 billion¹²). Critics also often cite the time it takes for a final FDA approval to market the product (usually quoting 10-15 years¹³). While these are important statistics, they speak only to the overall clinical trial process to obtain marketing approval and are not germane to the issue of access outside of clinical trials. Of course, a quicker development time leads to quicker access for the general public, but addressing that issue is beyond the scope of this article. Nevertheless, it is prudent for critics and supporters of the current early access process to correctly target their critiques. It is not correct, in this author’s opinion, to critique the expanded access process with arguments of how long and expensive final marketing approval is. They are two separate and distinct processes.

One correctly targeted argument, however, is regarding the paperwork required to complete the IND application. While the FDA says it can approve these applications quickly, preparing for and completing the application can be intimidating for patients and their physicians, even with the revised Form 3926.

The state-level ‘Right to Try’ movement 

Under the assumption that terminally ill patients face a different risk/benefit calculus than the general public, a dying patient should be able to try a treatment that may save his or her life regardless of the potential unknown serious side effects. The same assumption exchanges proof of efficacy for hope. Right to Try supporters assert that the desires of this individual outweigh, or at least can be addressed without interfering with the needs of the public; thus the government should not stand in a person’s way. They assert this case even if the treatment might a) fail to be effective; b) produce additional known or unknown adverse effects, further complicating the patient’s condition or quality of life; and/or c) accelerate their death. Some argue that these patients already have this right under the FDA’s expanded access program; California and Hawaii’s governors vetoed their state’s Right to Try legislation despite its passing their state congress with overwhelming support, although California did get some legislation passed a year after that veto.^14,15 

The intent, however, of state Right to Try laws is to accomplish this without having to go through the FDA (or any other government approving entity) citing a person’s constitutional right to medical autonomy.¹⁶ As a result, Right to Try legislations are intentionally crafted to not require FDA expanded access IND/protocol approval (along with its affiliated requirements such as institutional review board oversight) and to put in place state regulations governing the access. Although it is still a government entity setting the criteria for access and parameters, the legislation does not have the state-or any other government entity-taking on the role of a government body involved in the “yes/no” determination once the criteria is met. 

With the administration of unapproved therapies without the oversight of FDA and local IRBs, safety is a concern. Right to Try laws only include medicines/devices/biologics that have passed Phase I clinical trials and remain in development. Note, however, that Right to Try laws do not provide for other medicines available under Expanded Access that are not currently in clinical trials such as those with withdrawn INDs or under REMS. Advocates, therefore, point out that these drugs offer the same access that the FDA already allows clinical trial patients.¹⁷ However, a patient may be excluded from a study for many reasons. Those include known safety issues (a known serious adverse event affiliated with that patient’s condition/circumstances). They also include theoretical safety issues (a “just in case because we don’t know”) as well as purely scientific issues (i.e., exclusively for scientific integrity of the study and not for safety reasons). Under current state laws, if the treatment sought is no longer available to patients enrolled in clinical trials, it is no longer available to patients under Right to Try. 

While state Right to Try laws attempt to eliminate the FDA expanded access process as a required step, they fall short of addressing other common obstacles to access. No current Right to Try law requires the manufacturer to provide the product, few prohibit the manufacturer from charging for it if provided, and none require any insurance plan to cover it.¹⁸ By not addressing these obstacles, there has been critique of the banner of “Right to Try” as not really being a right to actually try but more so a “right to beg.”^19,20 In an example of this, a couple in which the 67-year-old husband had amyotrophic lateral sclerosis with two to three years to live moved back to Missouri from Florida after Missouri became the third state to pass a Right to Try law. It was their hope to obtain a specific investigational drug; after being turned down by the manufacturer, the couple learned that a “right” for a patient to try was not an obligation for the manufacturer to “give.”²⁰

Although the Goldwater Institute has model legislation it provides to state legislators to introduce, nearly each state has customized the laws, resulting in almost no two states having the same criteria and conditions.²¹ Universally, they do tout the elimination of the need for FDA’s permission and its accompanying obligations (i.e., IRB/ethical review board oversight). Ironically, however, most states have imposed criteria and obligations beyond that of the FDA (and even Goldwater Institute’s model legislation), making it longer and costlier for patients to access the product under Right to Try as opposed to expanded access. For example, several states require a second physician to confirm the terminally ill diagnosis, while the FDA only requires the patient’s physician to do so. Other common Right to Try requirements that go beyond FDA’s scope are listed in Table 2 below.²²

There are also other differences between the states (i.e., only about two-thirds offer some sort of immunity to the manufacturer; one-third require considerations for clinical trials first (e.g., site is 50 miles or 100 miles within patient’s home, etc.).²³

State law vs. federal law

In the face of conflicting federal laws, access to products under state Right to Try laws remains seemingly paralyzed. Constitutional scholars debate to what extent states may use their powers to protect their citizens’ rights, especially when state laws seemingly substitute for, add on to, and/or conflict with those enacted by the federal government. Ironically, those arguing either for or against expanded access being a state’s right to give point to many of the same precedent cases to support their cause. The most common cases are listed in Table 3.

Until these legal questions are resolved or federal laws are revised, stakeholders will need to determine whether a state Right to Try law provides a valid legal pathway for patient access of investigational products. If one accepts that Right to Try laws provide a valid separate and distinct pathway versus expanded access, then the patient need only to work with a physician to obtain a diagnosis and request the treatment directly from the manufacturer. This would be executed without FDA approval but, instead, under the criteria and conditions put forth in respective state laws. The burden on the manufacturers would be to be knowledgeable and adherent to individual state legislation. If, however, federal law supersedes state Right to Try laws and patients do not pursue treatment through FDA’s expanded access program, additional legal issues may arise from the shipment and/or administration under a state Right to Try law, as the Food, Drug and Cosmetics Act would prohibit such without FDA permission.²⁶ 

From a pragmatic standpoint, however, is the question of whether or not the FDA and/or the state are prepared to prosecute those they feel in violation of their respective policies and are willing to face any public consequences of doing so. More than likely, the court of public opinion, the media spin and the strategy of tort attorneys will pivot based on whether the use of the product was successful or not-and  be judged after the fact. The FDA, for example, may be criticized for sending a warning letter to a manufacturer who issued its experimental treatment under the Right to Try law when the product had a seemingly favorable outcome.

Conversely, if the product might have caused a lower quality of life and/or accelerated the patient’s death in their remaining days, the public might wonder where the FDA was. 

Regardless, many learned legal scholars have and will continue to argue the details of legal precedent and to what extent they apply to these new state laws. The potential “paralysis by analysis” comes at the misfortune of physicians, manufacturers, institutions and, most importantly, patients with terminal illness. Goldwater Institute CEO Darcy Olsen stated in a public hearing in February 2016 that it was aware of 28 patients that received products under state Right to Try laws.²⁷ This claim cannot be verified as none of the manufacturers, physicians or institutions have knowingly come forth to announce or explain their justification in not going through FDA channels. 

Anecdotal evidence, however, calls these potential success stories into question. For example, a patient, hearing the press surrounding their state passing a Right To Try law, may approach a physician/institution demanding products and upon receiving them claims a Right To Try success. In actuality, unbeknownst to the patient, the manufacturers and institutions went through the FDA’s expanded access. Should there, in fact, exist cases of administering under a state Right to Try law, justifications such as these need to be heard to help others feel comfortable with providing products either outside of or against the processes of FDA.

New attention at the federal level

If nothing else, the discussion around expanded access or compassionate use has received the attention of federal regulators. These agencies have the power to make uniform and broader reforms that could be wider-reaching than what the FDA or state Right to Try laws could do on their own. Although the recently passed 21st Century Cures Act includes many sections focused on improving time to product approval, there is one section that deals with expanded access directly. What was originally standalone legislation called the Andrea Sloan Compassionate Use Reform and Enhancement (CURE) Act passed as Section 3032 of the Cures bill. As part of this new legal requirement, a manufacturer must publicly post its expanded access policy for investigational drugs for “serious diseases or conditions.” The legislation only mentions drugs and does not offer reference to an equivalent requirement for medical devices. This posting must include (1) contact information regarding whom to make such request; (2) procedures for making a request; (3) the general criteria for request approval; and (4) length of time necessary to acknowledge receipt of request. The law would not require the manufacturer to provide the drug and the company could change the policy at any time. The posting would be required by the first initiation of a Phase II or Phase III study.  

One key piece of pending legislation that has recently been reintroduced is the Right to Try Act of 2017 (H.R. 878) and its accompanying Trickett Wendler Right to Try Act of 2017 (S. 204). These bills prohibit the federal government (i.e., the FDA) from prohibiting or restricting the production, manufacture, distribution, prescribing, dispensing, possession, or use of an experimental drug, biological product, or device that (1) is intended to treat a patient who has been diagnosed with a terminal illness; and (2) is authorized by, and in accordance with, state law. This act, if passed, would arguably eliminate the debate on federal vs. state governance of state Right to Try laws and thus revert to the individual states in these circumstances.

Regardless, the proposed Right to Try legislation at the federal level would give the backing of the state laws that the Right to Try advocates are looking for. Note, however, that previous recent attempts to get individual access outside of clinical trials at the federal level, such as the Access, Compassion, Care, and Ethics for Seriously Ill Patients Act,  introduced to Congress in 2005 and 2008, never received traction. With the presence of state laws and a White House statement regarding Vice President Pence’s support²⁸ (recalling his signing of Indiana’s Right to Try law as governor), perhaps these will provide a fundamental difference this congressional cycle. 

Although not yet reintroduced into Congress this session, one bill from the last session is noteworthy in showing the seriousness some legislators are taking on this issue. The Reciprocity Ensures Streamlined Use of Lifesaving Treatments (RESULT) Act strove to create the ability for reciprocity between the FDA and the equivalent competent authority of many other countries (e.g., Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa; or those countries in the European Union and the European Free Trade Association). The crux of the RESULT Act was that if there was a public health or unmet medical need in the U.S. to which one of these countries has an approved therapeutic, the manufacturer could apply to the FDA to market that product. The agency would then have 30 days to decline the request due to lack of safety/efficacy. Absent a denial, the product could be legally marketed but the FDA may also approve the drug within that 30 days, adding required postmarketing studies. The agency would have to report any denials to Congress monthly and Congress would have the authority to overturn any denials made. This bill represents a more aggressive stance for speed-to-market and could lead to new global development and sales strategies among drug and device manufacturers should it be reintroduced and passed. 

The remaining access obstacles 

While this article has detailed the FDA’s role in approving patient access, there are other substantial obstacles to access. These include a physician’s willingness to manage the case and a patient’s ability to pay for the therapy in the event the manufacturer does not provide it at no cost; insurance companies rarely cover investigational drugs. Probably the largest obstacle, however, is the manufacturer’s willingness to provide the therapy outside of controlled clinical trials. Neither the FDA, the Right to Try laws, or the pending legislation directly address the elimination or minimization of these obstacles. Nevertheless, there is some current softening. For example, in addressing physician resistance, state Right to Try laws generally offer some level of immunity to the physician for a good faith recommendation of an experimental therapy.²⁹ In parallel, FDA’s new Form 3926 helps streamline a physician’s time to complete the initial paperwork. 

As to softening manufacturers’ resistance, the FDA’s most recent guidance helps to address one of their core issues. It states that although adverse events must still be reported to the FDA even when the product is provided under expanded access, the agency reassures manufacturers that it will “understand the context” of these events as occurring in an uncontrolled environment when evaluating any new drug application (NDA).³⁰ The agency backs this up by reporting that out of more than 10,000 individual INDs and 1,000 commercial INDs, there have only been two instances of a temporary clinical hold from the individual IND, a rate of <.2%.³¹

Additionally, trade associations representing manufacturers are posting their guidance documents of support for pre-approval access through the expanded access program. These include Pharmaceutical Research and Manufacturers of America (PhRMA)’s new chapter in its Principles of Clinical Trials³² and the Biotechnology Innovation Organization’s (BIO) Principles on Expanded Access to Investigational, Unapproved Medicines.³³

Conclusion

Lawmakers, constitutional scholars, industry representatives, patient advocacy groups and patients themselves face ethical dilemmas over where to draw the line between regulation for the benefit of society and respect for individual autonomy. Wherever the line is drawn, it is crucial for all stakeholders to understand the laws-both federal and state-governing a terminally ill person’s access to investigational therapy. As regulations evolve and the demand for access to potentially life-saving treatment grows, manufacturers, healthcare providers and other key parties will need to confront the relevant practical and ethical issues associated with expanded access. While proponents of state law control such as the Goldwater Institute have been criticized in this process as advocating for laws of questionable authority and raising false hope, they have also elevated the national dialogue around the critical issue of pre-approval drug access.

David Vulcano, LCSW, MBA, CIP, RAC, is AVP & Responsible Executive, Clinical Research, Clinical Services Group, HCA; email: David.Vulcano@hcahealthcare.com 

References

1. Jonathan J. Darrow, Ameet Sarpatwari, Jerry Avorn, and Aaron S. Kesselheim. “Practical, Legal, and Ethical Issues in Expanded Access to Investigational Drugs”. N Engl J Med 2015; 372:279-286 January 15, 2015DOI: 10.1056/NEJMhle1409465

2. Vulcano, DM. “Comparing the State’s ‘Right to Try’ Acts: Effective Legislation or False Hope?” Policy and Medicine: Life Science Compliance Update. Volume 1, Issue 2, April 2015

3. 21CFR312.310

4. 21CFR312.315

5. 21CFR312.320

6. Expanded Access to Investigational Drugs for Treatment Use -Questions and Answers Guidance for Industry (June 2016) http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation /guidances/ucm351261.pdf 

7. Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators-Guidance for Industry (May 2015). https://www.fda.gov/downloads/Drugs/Guidances/UCM446695.pdf

8. Individual Patient Expanded Access Applications: Form FDA 3926- Guidance for Industry (June 2016). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation /Guidances/UCM432717.pdf

9. Brennan, Zachary. “FDA Official Dispels ‘100 Hours’ Myth on Time it Takes to Fill Out Compassionate Use Form.” Regulatory Affairs Professionals Society Website. http://www.raps.org/Regulatory-Focus/News/2016/05/17/24960/FDA-Official-Dispels-%E2%80%98100-Hours%E2%80%99-Myth-on-Time-it-Takes-to-Fill-Out-Compassionate-Use-Form/

10. “Individual Patient Expanded Access Applications: Form FDA 3926; Draft Guidance for Industry; Availability” https://www.regulations.gov/document?D=FDA-2015-D-0268-0001

11. “2013 Profile: Biopharmaceutical Research Industry.” Pharmaceutical Research and Manufacturers of America.

12. “Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion.” Tufts Center for the Study of Drug Development. Press Release: November 18, 2014. http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study

13. “2013 Profile: Biopharmaceutical Research Industry.” Pharmaceutical Research and Manufacturers of America.

14. “‘Right-to-try’ bill to help terminally ill access experimental drugs falls flat.” LA Times. Oct. 11, 2015. 

15. http://www.capitol.hawaii.gov/measure_indiv.aspx?billtype=SB&billnumber=2181&year=2016

16. “Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of their Treatment” Goldwater Institute Policy Report. February 11, 2014. http://goldwaterinstitute.org/en/work/topics/healthcare/right-to-try/everyone-deserves-right-try-empowering-terminally-/

17. ibid

18. Vulcano, DM. “Comparing The State’s ‘Right to Try” Acts: Effective Legislation or False Hope?” Policy and Medicine: Life Science Compliance Update. Volume 1, Issue 2, April 2015

19. “Bioethicist: ‘Right to Try’ Law More Cruel Than Compassionate.” NBC News. May 19, 2014. http://www.nbcnews.com/health/health-news/bioethicist-right-try-law-more-cruel-compassionate-n108686

20. “Missouri’s ‘Right to Try’ law no guarantee patient will get experimental drugs.” St. Louis Post-Dispatch. May 20, 2015. http://www.stltoday.com/news/local/metro/missouri-s-right-to-try-law-no-guarantee-patient-will/article_05c07958-5217-5c3f-9f15-1a43c8a3e740.html

21. Vulcano, DM. “Comparing The State’s “Right to Try” Acts: Effective Legislation or False Hope?” Policy and Medicine: Life Science Compliance Update. Volume 1, Issue 2, April 2015

22. ibid

23. ibid

24. GONZALES V. OREGON (04-623) 546 U.S. 243 (2006) 368 F.3d 1118, affirmed

25. Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach, 495 F.3d 695 (D.C. Cir. 2007), cert denied 552 U.S. 1159 (2008)

26. FD&C Act, sec. 301(a); 21 U.S.C. 331(a)].

27. “Connecting Patients to New and Potential Life Saving Treatments.” U.S. Senate Committee on Homeland Security and Governmental Affairs. February 25, 2016. http://www.hsgac.senate.gov/templates/watch.cfm?id=90AF867B-5056-A066-607D-BD6E66C0A41B 

28. https://www.whitehouse.gov/the-press-office/2017/02/07/readout-vice-presidents-meeting-right-try-advocates

29. Vulcano, DM. “Comparing The State’s “Right to Try” Acts: Effective Legislation or False Hope?”. Policy and Medicine: Life Science Compliance Update. Volume 1, Issue 2, April 2015

30. Expanded Access to Investigational Drugs for Treatment Use -Questions and Answers Guidance for Industry (June 2016) http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation /guidances/ucm351261.pdf

31. FDA Presentation at Reagan-Udall Foundation Public Workshop: Developing an Expanded Access Navigator for Individual Patient Access to Investigational Drugs, May 16, 2016. http://www.reaganudall.org/wp-content/uploads/2016/04/Klein_Expanded-Acces-to-Investigational-Drugs-and-Biologics.pdf

32.

33. https://www.bio.org/articles/bio-principles-expanded-access-investigational-unapproved-medicines