The Challenges of Clinical Trial Design in Evaluating HIV Antiretroviral Use in Heavily Pre-Treated Patients

1. The Challenges of Clinical Trial Design in Evaluating HIV Antiretroviral Use in Heavily Pre-Treated Patients The Community Perspective Carlton Hogan, University of MN FDA Antiviral Advisory Committee January 11, 2001

2. Who is a “Salvage Patient”? • Single PI failure? • Multiple PI failure? • No new RTIs to substitute? • NNRTI naive? • Transmission of resistant virus? • Community feedback - “salvage” not a very popular term

3. Coalition for Salvage Therapy • Ad Hoc coalition, with members from TAG, Project Inform, ACT-UP, FAIR, NAPWA, NMAC etc. • Focusing on patients with few or no viable treatment options • Focus on trying to facilitate inter-sponsor collaborative research • And at least a limited expanded access/compassionate usage for those with no present options

4. Intensification Designs • On the whole, we are uncomfortable about trials that simply add one new agent to a failing regimen - a sort of “virtual monotherapy” • Such designs may not only provide inadequate care, provoking rapid viral resistance,but may prejudice later treatment options. • Intensification as a basic principle of therapy has an inherent futility. We are already hearing reports of patients taking eight or nine drugs as “Mega-HAART”. How many people can tolerate this? For how long?

5. Monotherapy/”Virtual” Monotherapy • While we recognize that there may be some situations, particularly in pharmacodynamic studies where a single agent must be used, wherever possible such studies should be done in HIV negative volunteers. • Where it is absolutely necessary to use HIV+ subjects, exposure to monotherapy or virtual monotherapy should be restricted to the shortest possible intervals. • This may be overly optimistic, but it would be very nice to see some kind of longer term follow-up to assess the risk of conducting such studies.

6. Concentration Controlled Trials • In the past few years, a sophisticated and nuanced set of complications have come to the forefront as potential key determinants of successful treatment, including • Cytochrome p450 inhibition and/or induction, • Protein binding, • p-2 glycoprotein, • Impaired gastrointestinal function • Differences between intercellular and intracellular concentrations • The effects of hepatitis and other co-morbidities • Other drug and food interactions than those listed above

7. Open questions • What are the implications of transient “dips” below therapeutic levels? • Can resistance be overcome by increased drug concentration? • What are the long term sequelae of blockading Cytochrome p450 with Ritonavir for years? To what degree does this raise the risk of toxicities from concomitant medications, or even foods?

8. Open Questions II • What is the variance between individuals in how drug levels vary over the day? • Is it the case that a balance needs to be struck between QD dosing, and hopefully improved adherence and potential increases in drug concentration variations? • To what degree do “host resistance” phenomena determine treatment effect e.g. does long term nucleoside treatment impair one’s ability to phosphorylate nucleosides? • Will parenteral-only treatments be accepted? Will compliance differ greatly from that of oral compounds? What will the virologic impact be?

9. Trial Design Priorities • There are patients out there who have been exposed to all three classes of drugs, and are incapable of achieving successful virologic control with gents available today • Transmission of virus resistant to all three classes has been documented • As the HIV+ population lives longer, the opportunities of acquiring resistance dramatically increase • Assuming today’s treatments are even moderately successful, we will continue, for the foreseen future, to see patients with longer and longer exposure to more different drugs

10. True Salvage Patients • We have recently seen a number of industry conducted purported “salvage” trials with strong caveats e.g. no prior NNRTI exposure, or no more than two previous PIs • While we certainly do not deny the need of new therapies for these people, who may be facing their one last good opportunity, our priority is the triple-class exposed patient • It is in this subset of patients the most poignant dilemmas manifest, and the most innovative trial designs will be required

11. Designs for the True Salvage Patient • It is our strong contention that designs that offer only one novel agent are unlikely to succeed, and may compromise future use of that agent in a combination. • While it has never been an easy task to coordinate trials with multiple pharmaceutical sponsors, our conversations with industry have been very promising • Several companies have expressed willingness to collaborate on salvage studies. But they don’t want to compromise their chances of registration - ideally, they would like the data from such trials usable to support approval • It is ABSOLUTELY KEY that FDA proactively offer clear and unambiguous guidance with regard to these issues.

12. Background Therapy in Salvage Trials • The heterogeneity of previous treatment regimens makes it impossible to construct a single background therapy ( i.e. like nucleosides in a PI trial) for all patients • We feel it is important that any background therapy needs to be flexible, and individually optimized, using phenotypic and genotypic resistance. • Preservation of future treatment options, primary and background, should always be a strong consideration, and might even make a useful secondary endpoint.

13. The “Factorial on Top of Optimized Background Therapy” concept • Assuming that we can get two or more sponsors to support a salvage trial, we would like to see that trial produce the maximum useful information, while also doing it’s best to assure patient safety. • In the case of two experimental drugs, such a study might look like this: OBT vs OBT+Drug A vs. OBT+Drug B vs OBT+A+B Such a design allows us to examine the individual contribution of each drug, as well as the combination.

14. Better Yet • There are potential problems with such a design using only two experimental agents. There are some in the community who would object to the “OBT alone” arm, and two of the other arms offer only one experimental agent • So our primary preference is a modified factorial on top of OBT • By “modified” factorial, we mean that the factors containing less than two experimental drugs are omitted, but we still have the opportunity to compare all the arms taking a specific drug to all those who aren’t

15. The Consensus Favorite • 3 new drugs, A, B, and C • (all arms described are on top of OBT) • Traditional factorial • nothing • A • B • C • A+B • A+C • B+C • A+B+C • “Modified” Factorial • A+B • A+C • B+C • A+B+C

16. Advantages and Disadvantages Advantages • May offer better chance of virologic control in every arm • May delay further resistance to study agents and BG Tx • Allows immediate insight into the relative merits of various combinations • Very attractive to potential participants Disadvantages No true control arm May be difficult to conclusively ascribe adverse events to one agent If even this potent combination does not achieve virologic control, patients may have to endure more toxicities, without commensurate benefits

17. Endpoints • Few patients may achieve undetectability: change in HIV RNA may be more relevant than % undetectable • The classic clinical composite endpoint “progression or death” may not be as relevant in persons taking many drugs. It may be worth considering composites that also incorporate major toxicities, like cardiovascular disease • A secondary endpoint should be rates of genotypic and phenotypic resistance, to both the study agent(s) and the BG Tx • Since we are (in general) defining salvage populations based on virologic response (or rather, lack thereof) it may be less productive to even use HIV RNA as a primary endpoint - there are clearly people who remain healthy despite elevated HIV RNA - theories about “crippled virus” abound. It is worth considering CD4 as the primary surrogate outcome. After all it is clearly the best predictor of short to mid term risk

18. What We Need From the Agency • Sponsors need clear, unambiguous guidelines about which sorts of novel study designs may be used in support of an NDA, perhaps even overt encouragement to seek salvage indications. • To open a discussion into incentives for research into smaller subpopulations: pediatrics, salvage, IDUs, etc • A commitment to encourage industry to do meaningful expanded access programs, especially in Salvage populations. And preferably not just scant weeks before licensure!! • Co-enrollment in expanded access programs should become common. We heartily applaud several companies, notably Abbott, for their leadership in this area.

19. What We Need From the Agency • Long term follow-up. Long term follow-up in AIDS trials has been a disgrace. Even before the accelerated approval regulations were rewritten, few sponsors fulfilled their post-marketing requirements. • Virtually none of the major PI toxicities were identified before, or even shortly after licensure (lipodystrophy, CVD, Insulin resistance, etc) • In some cases (e.g. AZT myopathy) toxicities were not clear until years after approval. This is not acceptable. • Especially in Salvage patients, where there may be no virologic indication of response, it will be important to see if there is clinical benefit anyway, or conversely, if treatments are just killing people